IntroductionHumoral immunity is an important component of the adaptive immune response, orchestrated by B lymphocytes through the production of antigen-specific antibodies.1 This arm of immunity is primarily responsible for the elimination of extracellular pathogens from body fluids (e.g., blood and lymph) and the neutralization of microbial toxins. Upon recognizing a specific antigen via the B cell receptor (BCR) and with assistance from T follicular helper (TFH) cells, B cells become activated and differentiate into plasma cells (PCs) that produce large quantities of specific antibodies.2 These antibodies neutralize pathogens directly, facilitate their phagocytic clearance through opsonization, or activate the complement cascade to amplify and resolve the immune response. The proper execution of these functions thus depends on the precise regulation of B-cell development and activation. Beyond the acute response, a subset of activated B cells gives rise to long-lived plasma cells (LLPCs) and memory B cells (MBCs) that sustain antibody titers and enable rapid recall responses, forming the cellular basis of durable immunity and vaccine efficacy.3,4Epigenetics encompasses a class of mechanisms that regulate gene expression heritably or reversibly without altering the underlying DNA sequence. These mechanisms include DNA methylation, posttranslational histone modifications, and regulation by noncoding RNA (ncRNA)5,6,7—all of which act in concert to dynamically modulate transcriptional programs, thereby shaping cellular identity and differentiation states.8 These marks are deposited, removed, and interpreted by dedicated “writer”, “eraser”, and “reader” proteins, and the recognized repertoire has expanded to encompass diverse RNA modifications and ATP-dependent chromatin remodeling.9,10,11 Epigenetic mechanisms are integral to both the development and effector functions of the immune system.12,13,14,15 In B lymphocytes, stage-specific epigenetic modifications orchestrate precise patterns of gene activation and silencing, guiding lineage commitment and functional specialization.8,16,17 During the humoral immune response, pivotal processes—including class switch recombination (CSR), somatic hypermutation (SHM), and the differentiation of activated B cells into MBCs and PCs—are all governed by dynamic epigenetic reprogramming.8,18,19 Perturbation of these regulatory programs may produce aberrant antibody responses and immune dysregulation, manifesting as pathogenic autoantibody production and B-cell-driven autoimmune disease.16Over the past decade, rapid advances in epigenomic technologies—including single-cell and base-resolution profiling of DNA and RNA modifications, genome-wide mapping of chromatin accessibility, and analysis of three-dimensional genome organization—have transformed our ability to dissect the epigenetic landscape of B cells with unprecedented resolution (Table 1).20,21,22,23,24,25 These approaches have revealed that each transition in B-cell development and differentiation is accompanied by extensive, stage-specific remodeling of DNA methylation, histone marks, and chromatin architecture.26,27,28 In parallel, aberrant epigenetic programs have emerged as central drivers of diverse B-cell disorders, ranging from malignant transformation in lymphoma and leukemia to pathogenic autoantibody production in systemic autoimmunity.29,30,31 The translational relevance of these insights is underscored by a growing arsenal of agents targeting epigenetic regulators—such as DNA methyltransferase and histone deacetylase inhibitors—that have entered clinical oncology and are now being explored in immune-mediated diseases.7,32,33 Nevertheless, the epigenetic circuits operating across the successive stages of the humoral response and the mechanisms by which their dysregulation gives rise to specific pathologies remain fragmented and incompletely integrated, highlighting the need for a unified mechanistic framework.Table 1 Overview of contemporary epigenomic profiling technologies: methods, resolution, and key featuresFull size tableThis review summarizes current evidence and identifies open questions about the epigenetic mechanisms governing humoral immunity and their functional consequences across successive stages of B-cell biology. Tracing the developmental trajectory from early lineage commitment and antigen recognition through germinal center (GC) reactions, antibody production, and immunological memory formation, we delineate the major epigenetic programs—including DNA methylation, histone modifications, chromatin remodeling and accessibility, RNA modifications, and ncRNA regulation—that orchestrate gene expression and B-cell fate at each transition. We further address how perturbation of these programs drives immune-related pathologies, including B-cell malignancies, metabolic and cardiovascular diseases, systemic autoimmune diseases, and infectious diseases, and evaluate the translational potential of epigenetic modulators as therapeutic agents and epigenetic signatures as biomarkers. In addition, we examine the contribution of sex-biased epigenetic mechanisms—particularly XIST-dependent X-chromosome inactivation (XCI) and its dysregulation in atypical B cells—to the female-skewed incidence of autoimmune disease. By integrating mechanistic insights across these dimensions, this review aims to provide a conceptual framework for future investigation and to inform the development of epigenetics-based therapeutic strategies for B-cell-driven diseases.Humoral immunityB-cell developmentThe study of B cells and humoral immunity has a rich history spanning over a century. In the late 19th century, early microscopists observed mitotic foci in lymphoid tissues, which they termed GCs.34 In 1890, Emil von Behring and Shibasaburo Kitasato35 identified a serum-derived substance that conferred protection against disease upon passive transfer—later designated “antibody”. In the early 20th century, Paul Ehrlich36 proposed a theoretical framework for humoral immunity through his side-chain theory of antibody formation. Decades later, Burnet’s37 clonal selection theory explained how the immune system generates antibodies against virtually any foreign antigen while maintaining self-tolerance. In the 1960s, Max Cooper demonstrated that surgical removal of the bursa of Fabricius—the primary site of B-cell development in birds and the origin of the “B cell” nomenclature—completely abolished antibody production, establishing the essential role of these lymphocytes in humoral immunity.38 Building on this foundation, Tonegawa subsequently demonstrated the somatic V(D)J recombination of immunoglobulin genes39—a RAG-dependent process40—which can theoretically generate more than 1011 distinct immunoglobulin (Ig) variants,41 providing the molecular basis for the vast antibody repertoire. Today, vaccines that protect against infectious diseases fundamentally rely on B-cell activation, and therapeutic antibodies—including immune checkpoint blockade agents—are developed using monoclonal antibody platforms. Conversely, disruption of B-cell function can have devastating consequences for immune defense and homeostasis.The Ig molecule consists of two heavy chains and two light chains linked by disulfide bonds. B-cell development proceeds through sequential Ig rearrangements. D-J rearrangement of the heavy chain locus occurs in common lymphoid progenitors (CLPs) and pre-pro-B cells,42 followed by V-DJ rearrangement in pro-B cells, which generates a functional μ heavy chain.43 In large pre-B cells, this μ heavy chain associates with the surrogate light chain and Igα/β (CD79a/b) co-receptors to form the pre-B cell receptor (pre-BCR) on the cell surface.44 Driven by robust pre-BCR signaling, B cells proliferate and progress to the small pre-B-cell stage.44 Resting small pre-B cells subsequently undergo V-J rearrangement of the Ig light chain,45 producing a fully functional BCR expressed as membrane-bound IgM (mIgM) on the surface of immature B cells. To prevent autoreactivity, self-reactive immature B cells in the bone marrow primarily undergo receptor editing, with clonal deletion or anergy as alternative outcomes depending on self-antigen form and signal strength.46 Following development in the bone marrow (BM), surface IgM-expressing immature B cells migrate to the spleen, where they progress through transitional B-cell stages (termed T1 and T2) before maturing into long-lived follicular (FO) or marginal zone (MZ) B cells.46 In mice, the T3 compartment, rather than serving as a conventional precursor of mature B cells, consists largely of anergic B cells that fail to progress into the mature B-cell pool.46 FO B cells are the predominant subpopulation and reside in the lymphoid follicles of the spleen and lymph nodes. MZ B cells are located immediately adjacent to the marginal sinus of the spleen, ideally positioned to respond to blood-borne pathogens and particulate antigens.47 Thus, B-cell development encompasses both antigen-independent and antigen-dependent selection phases, which are tightly regulated by signal transduction. Beyond these classical developmental sites, recent evidence indicates that B-cell development and selection can occur at the central nervous system (CNS) borders, particularly in the meninges supplied by calvarial bone marrow: Colonna and colleagues48 demonstrated that the B-cell population in the murine meninges develops from skull BM, and Wang and colleagues49 identified pro-B, pre-B, and immature B cells in the meninges. These findings suggest that the murine meninges harbor a specialized immune niche at the CNS border that supports local B-cell development and selection.In addition to FO B cells and MZ B cells, a third population of mature B cells—B1 cells—is found in the spleen, peritoneal cavity, and pleural cavity, a distribution ideally suited for surveillance of environmental pathogens.47 Although debates regarding their developmental origins persist, B1 cells are largely believed to have a distinct hematopoietic origin in the fetal liver, and early lymphocyte proliferation in the embryo appears to favor B1-cell development. It has also been shown that B1 cells do not require progenitors distinct from those of B2 cells and that a B1-characteristic BCR can reprogram B2 cells into B1-like cells.50 This tissue-specific localization underlies the capacity of B1 cells and MZ B cells to mount rapid responses to T cell-independent (TI) antigens, such as bacterial components, whereas FO B cells are primarily specialized for T cell-dependent (TD) responses to protein antigens, although they are also capable of responding to TI antigens.3 In recent years, additional functionally distinct B-cell subsets have attracted considerable attention, including age-associated B cells (ABCs),51 regulatory B cells that suppress inflammation through various mechanisms,52 and B lymphocytes within tumor-associated tertiary lymphoid structures (TLS).53,54Initiation of humoral immunityHumoral immunity is initiated when rare antigen-reactive B cells encounter antigens. Such antigen–B cell encounters occur primarily in secondary lymphoid organs (SLOs), including the spleen, lymph nodes (LNs), and Peyer’s patches. These tissues filter distinct body fluids—the spleen filters blood, LNs filter lymph, and Peyer’s patches sample mucosal contents. In LNs and Peyer’s patches, high endothelial venules (HEVs) continuously recruit naïve lymphocytes from the blood, while antigens arriving via afferent lymphatics and conduits are captured and concentrated on follicular dendritic cells (FDCs) within lymphoid follicles, bringing lymphocytes and antigens together for productive activation.55 Although the cells that initially acquire, transport, and display antigens vary among lymphoid tissue types, the fundamental principle of presenting intact antigens for B-cell recognition and endocytosis holds true. The spleen filters blood-borne pathogens, whereas other secondary lymphoid tissues sample pathogens from localized anatomical sites (e.g., skin or internal organs).56,57 In LNs, for example, subcapsular sinus (SCS) macrophages acquire particulate antigens from the afferent lymph and relay them to follicular B cells at the follicle border.55 At the center of lymphoid follicles are FDCs (Fig. 1),58 specialized stromal cells that retain and display antibody- or complement-coated antigens on their dendritic processes. Unlike most antigen-presenting cells, FDCs are nonphagocytic and retain intact antigens on their surface for extended periods—sometimes weeks.58 Although long difficult to characterize, the FDC transcriptome has been substantially illuminated by recent single-cell RNA sequencing (scRNA-seq) studies.59Fig. 1Full size imageTwo phases of the humoral immune response: primary activation and germinal center reaction leading to long-term immunity. Top panel: The humoral immune response proceeds in two coordinated phases that ensure both immediate protection and durable immunological memory. Phase 1: Primary response and initial B-cell activation. Naïve B cells are activated upon encountering antigens within secondary lymphoid organs. In the T-cell zone, dendritic cells (DCs) process and present antigens to CD4⁺ T cells. Simultaneously, in the B-cell zone (primary follicle), naïve B cells recognize intact antigen via their B-cell receptors (BCRs), typically presented by subcapsular sinus (SCS) macrophages and conventional dendritic cells (distinct from FDCs) at the follicle border; FDCs subsequently retain antigen within the germinal center (GC) to support affinity maturation in phase 2. Following antigen recognition, activated B cells migrate to the interfollicular region, where they engage in cognate interactions with T follicular helper (TFH) cells. This process involves MHC class II–peptide presentation to the T cell receptor (TCR) and co-stimulatory signaling (e.g., CD40–CD40L interaction). Activated B cells then differentiate into short-lived plasma cells (SLPCs) or memory B cells (MBCs), or enter early proliferative stages, leading to GC formation. Phase 2: GC reaction and generation of long-lived plasma cells (LLPCs) and MBCs. The GC is a dynamic structure composed of two compartments. In the dark zone, proliferating GC B cells (centroblasts) undergo somatic hypermutation (SHM) to diversify their BCRs. Class switch recombination (CSR) is not restricted to the dark zone and can begin before GC formation, including in extrafollicular responses. Centroblasts then migrate to the light zone as centrocytes, where they compete for antigen presented by FDCs and interact with TFH cells. Only B cells with high-affinity BCRs receive survival signals, while those with low affinity or autoreactivity undergo apoptosis. Positively selected B cells can differentiate into (1) LLPCs, which migrate to the bone marrow and provide sustained antibody secretion, or (2) MBCs, which respond rapidly to future antigen exposure; B cells that fail selection undergo apoptosis. This selection process underpins affinity maturation and establishes a robust secondary immune response. Bottom panel: Key molecular regulators governing each step of B-cell activation, GC dark-zone and light-zone transitions, and the three possible fates of GC B cells (PC differentiation, MBC formation, or apoptosis). Figure created using Adobe Illustrator (Adobe Inc.)B-cell activation in LNs occurs within distinct anatomical compartments (Fig. 1): (1) the T-cell zone (paracortex), where T cells are recruited from the bloodstream via HEVs through CCL21–CCR7 signaling; (2) the interfollicular region, where early T–B cell interactions occur; and (3) the B-cell follicle, enriched with IgM+ IgD+ naïve B cells and bordered by the subcapsular sinus. B cells enter LNs through HEVs with the aid of CCL21–CCR7 and CXCL12–CXCR4 signaling and then migrate to follicles guided by CXCL13—a chemokine produced by FDCs and follicle-associated stromal cells—acting through CXCR5. Within the follicle, B cells scan for antigens presented by SCS macrophages and dendritic cells (DCs, distinct from FDCs).55 Absent cognate antigen, B cells exit lymphoid tissues in response to sphingosine-1-phosphate (S1P)–S1PR1 signaling. B cells exit the spleen directly into the vasculature, whereas egress from LNs and Peyer’s patches occurs via efferent lymphatics. Circulating B cells can reach distant lymphoid tissues within minutes to continue immunosurveillance.60B-cell activation and generation of long-term humoral immune memoryLong-term humoral immunity following infection relies on two GC-derived cell types: LLPCs, which continuously secrete antibodies, and MBCs. Upon antigen re-encounter, MBCs rapidly proliferate and differentiate into antibody-secreting cells (ASCs). Notably, MBCs can adapt to antigenic variation caused by viral mutations and mediate cross-reactive responses to related viruses. For example, during human immunodeficiency virus (HIV) infection, neutralizing antibodies co-evolve with mutant viral epitopes;61 MBCs initially generated against dengue virus can cross-react with Zika virus;62 and SARS-CoV-2 infection elicits MBCs that mature and persist over time, contributing to durable humoral protection upon re-exposure.63 B-cell activation requires two signals: the first is delivered by BCR engagement with cognate antigen, and the second is typically provided by CD40L on T helper cells. This second signal can alternatively be delivered through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) on B cells—a mechanism characteristic of TI responses.64 Both TD and TI activation promote B-cell proliferation and can generate MBCs and PCs through GC-independent pathways. Several studies have demonstrated that long-lived MBCs, short-lived plasma cells (SLPCs), and LLPCs can be generated through both GC-independent and TI mechanisms.64,65,66Upon antigenic stimulation via FDCs, B cells upregulate CCR7 and Epstein-Barr virus–induced gene 2 (EBI2, also known as GPR183), driving their migration from the primary follicle to the T–B border (Fig. 1).67 There, B cells encounter T cells that have migrated from the T-cell zone after receiving antigen from DCs. These T cells differentiate into pre-T follicular helper (pre-TFH) cells, a CD4+ subset expressing the transcription factor BCL6. Pre-TFH cells upregulate CXCR5 and downregulate CCR7, directing their migration toward the T–B border.4,68 Upon initial activation, T and B cells form stable conjugates in the interfollicular zone—the first round of T-cell help. These interactions depend on CD40L–CD40 engagement and TCR recognition of peptide–major histocompatibility complex (MHC) II complexes on B cells, driving proliferation of both cell types and germline transcription at the Cγ1 and Cε loci of the immunoglobulin heavy chain (IgH).69,70 Around day 3 of the immune response in the spleen, activated B cells adopt one of three fates (Fig. 1): (1) continued proliferation toward GC entry; (2) apoptosis; or (3) extrafollicular differentiation into SLPCs or GC-independent MBCs.70,71 Extrafollicular PCs generated during this phase secrete large amounts of low-affinity IgM, providing early pathogen protection. Although a substantial fraction of these extrafollicular PCs remain IgM-secreting, CSR can occur in the extrafollicular compartment, and SLPCs of switched isotypes also arise from this response;72 SLPCs accumulate in the splenic red pulp and LN medullary cords, with lifespans generally limited to the duration of infection;72,73 a small proportion give rise to LLPCs.74 With robust CD4+ T-cell help, activated B cells can also differentiate into GC-independent MBCs with limited CSR, predominantly generating IgM+ CD73- cells.75 These early MBCs arise from multipotent precursor cells that later give rise to GC-dependent, class-switched MBCs.75 In BCL6-deficient mice, naïve B cells fail to form GCs but can still generate MBCs through this pathway; however, these cells do not undergo SHM and cannot give rise to LLPCs.76 This early phase constitutes the first stage of immune memory, during which affinity-based selection plays a relatively minor role in fate determination.72The second phase of immune memory focuses on the generation and selection of high-affinity B cells. Following initial activation, B cells migrate to the outer follicle via EBI2 signaling in response to oxysterol ligands from peripheral stromal cells (Fig. 1).77 Concurrently, pre-TFH cells enter the follicle, upregulate BCL6, and mature into TFH cells, accompanied by increased PD-1 and GL7 expression. Around day 4 of the immune response, B cells downregulate EBI2 and upregulate BCL6. Guided by CXCR5 and sphingosine-1-phosphate receptor 2 (S1PR2), B cells migrate into the follicle and localize to its center, although the precise mechanisms governing this localization remain incompletely understood.78 Secondary follicles then form, and early GCs emerge, with B cells differentiating into centroblasts. Over the next two days, B cells and TFH cells expand rapidly, filling the FDC network. This growth drives GC expansion until approximately day 7, when mature GCs are established. The mature GC is structurally divided into the dark zone (DZ), light zone (LZ), and surrounding mantle zone, distinguished by differential expression of CXCR4, CD83, and CD86 (Fig. 1). DZ identity is enforced by FOXO1, whose transcriptional activity is preserved in the DZ because BCR-downstream phosphoinositide 3-kinase (PI3K)/AKT signaling is transiently attenuated; in the LZ, BCR- and CD40-driven PI3K activation phosphorylates and inactivates FOXO1, extinguishing the DZ-defining transcriptional program and licensing centrocyte identity.79 The DZ—named for its dense histological appearance due to the high nuclear-to-cytoplasmic ratio of rapidly dividing cells—comprises CXCL12-producing reticular cells and centroblasts, which are recruited via CXCR4-mediated chemotaxis.80 Centroblasts proliferate and undergo SHM to diversify BCR sequences before exiting the cell cycle and migrating to the LZ. At the peak of the GC response, centroblasts divide approximately every 6 hours.2 During proliferation, these cells express minimal surface immunoglobulin (sIg), which is upregulated only upon cell cycle exit. Crossing the CXCL13 gradient produced by FDCs, centroblasts downregulate CXCR4 and upregulate CXCR5, entering the LZ as centrocytes.80,81 The LZ harbors centrocytes, TFH cells, FDCs, macrophages, and T follicular regulatory (Tfr) cells. Centrocytes capture FDC-displayed antigens and present peptide–MHC II complexes, competing for TFH cell help to obtain survival and differentiation signals. Tfr cells regulate the GC response by modulating TFH cell proliferation, B-cell metabolism, and cytokine production.82GC B cells can adopt one of three fates (Fig. 1): (1) DZ re-entry: Some GC B cells upregulate c-Myc, promoting AP4 expression and CXCR4 upregulation, enabling DZ re-entry.83,84,85,86 Upon re-entry, c-Myc is downregulated, and glycogen synthase kinase 3 (GSK3) governs mitochondrial biogenesis and reactive oxygen species (ROS) homeostasis.83,84,85,86,87 In the DZ, these cells undergo further proliferation, SHM, and CSR—with recent evidence indicating that CSR may initiate as early as 1.5 days post-immunization, prior to GC formation.73 Iterative DZ–LZ migration permits multiple rounds of proliferation and affinity-based selection;2 c-Myc and REL are required for this shuttling and GC maintenance,2 while the MYC–MIZ1 complex suppresses premature MBC differentiation.88 (2) LLPC differentiation: GC B cells whose BCRs have acquired mutations that confer sufficiently high affinity can differentiate into LLPCs that home to the bone marrow and secrete antibodies for years—or even a lifetime—without further antigen exposure.66,89 (3) MBC differentiation: Other GC B cells exit as MBCs that persist in a quiescent state in secondary lymphoid organs and peripheral tissues, enabling rapid antigen re-encounter.90,91,92 Upon secondary antigen exposure, MBCs can rapidly differentiate into ASCs or re-enter GCs for additional SHM and selection (Fig. 1).Major mechanisms of epigenetic regulationAccording to the central dogma of molecular biology, genetic information stored in DNA is transcribed into RNA and subsequently translated into proteins that execute cellular functions. Epigenetic mechanisms influence gene expression at the transcriptional and posttranscriptional levels, thereby shaping cell fate decisions and organ development. Many epigenetic states are dynamic and potentially reversible, although their stability and reversibility vary by mechanism and cellular context.93 Three classes of proteins govern this system: “writers” deposit chemical marks on DNA or histones; “erasers” remove them; and “readers” contain specialized domains that recognize these marks and translate the epigenetic code into functional outcomes. The major types of epigenetic modifications include DNA methylation, histone modifications, chromatin regulation, RNA modifications, and ncRNA regulation. Technological innovations over the past decade have transformed our ability to dissect these mechanisms (Table 1). Single-cell and spatial profiling, long-read sequencing, and multi-omics integration now enable mapping of epigenetic modifications with unprecedented resolution—from single-nucleotide precision to native chromatin context—revealing mechanistic insights inaccessible to conventional methods. Each modification type is discussed in turn.DNA methylationDNA methylation involves the addition of methyl groups to specific DNA bases. Primary targets include cytosine and adenine, yielding 5-methylcytosine (5mC) and N6-methyladenine (6-mA), respectively, each catalyzed by distinct methyltransferases and playing diverse biological roles.94,95 Among these, 5mC is the most prevalent and best characterized in mammals, accounting for approximately 4% of total cytosines in the human genome. It occurs predominantly at CpG dinucleotides and plays a key role in regulating gene expression, genome stability, embryonic development, and disease pathogenesis (Fig. 2).96,97 CpG sequences are either dispersed throughout the genome or clustered into CpG islands, which are typically located in promoter regions and maintained in a hypomethylated state.96 These hypomethylated islands serve as hotspots for transcription factor binding and are intimately involved in transcription initiation and enhancer regulation.98,99 Beyond transcriptional regulation, 5mC undergoes dynamic changes during nervous system development; CG and CH (H = A, T, or C) methylation show developmentally regulated patterns associated with neuronal gene regulation.100 5mC is also implicated in aging: methylation patterns correlate strongly with species lifespan—females typically exhibit longer lifespans, a difference that is captured in sex-specific methylation signatures.101Fig. 2Full size imageMajor types of epigenetic modifications and their associated modifying enzymes. Epigenetic regulation encompasses a broad array of molecular mechanisms that modulate gene expression without altering the underlying DNA sequence. These include DNA modifications (e.g., methylation), histone modifications (e.g., acetylation, methylation, ubiquitination), RNA modifications (such as m6A, m5C, and m7G), chromatin remodeling, and ncRNA-mediated regulation. Together, these processes shape chromatin architecture and regulate gene expression at the transcriptional and posttranscriptional levels. Many chemical epigenetic marks are dynamically regulated by writers, erasers, and readers, although reversibility, heritability, and the applicability of this enzyme-based framework vary among DNA, histone, RNA, chromatin-remodeling, and ncRNA mechanisms. This coordinated enzymatic interplay underpins cellular differentiation, development, immune function, and disease pathogenesis. Figure created using Adobe Illustrator (Adobe Inc.)6-mA has recently emerged as a functionally relevant DNA methylation mark.95 First identified in mammalian and vertebrate genomes between 2015 and 2016102,103 and subsequently characterized in mammalian mitochondrial DNA in 2020,104 6-mA is prevalent and essential for survival and stress adaptation in lower eukaryotes such as Tetrahymena (0.66%),105 plants,106 and C. elegans.107 In mammals, its abundance is highly context-dependent: mitochondrial DNA contains approximately 20–400 ppm;104 embryonic stem cells harbor low but functionally significant levels (approximately 6–7 ppm) associated with gene silencing;103 stress and disease states show localized enrichment;108,109 while nuclear DNA in adult tissues contains extremely low levels (200 nt) operate through distinct compartment-specific mechanisms: in the nucleus, through cis-acting regulation of chromatin architecture or neighboring gene transcription;226 in the cytoplasm, through direct interactions that modulate protein–protein interactions, protein conformation, or enzymatic activity.227 circRNAs form covalently closed loops that resist exonuclease-mediated degradation and retain this stability in body fluids and tissues, making them attractive biomarker candidates.228 They regulate transcription, translation, and posttranslational modification, modulate immune responses, and interact with mRNAs, miRNAs, and proteins.229,230Epigenetic modifications in humoral immunityThe epigenetic mechanisms introduced above—DNA methylation, histone modifications, RNA modifications, chromatin remodeling and accessibility, and ncRNAs—collectively orchestrate B-cell development, activation, and differentiation during humoral immune responses. In this section, we examine how each of these regulatory layers contributes to specific stages of B-cell biology, from early lineage commitment through GC reactions to terminal differentiation into PCs and MBCs.DNA methylationDynamic changes in DNA methylation are critical for B-cell fate determination and functional maturation (Fig. 3). B-cell lineage commitment and early development require specific DNA methylation patterns precisely regulated by DNMTs and TET family demethylases.26 TET2 and TET3 serve as the predominant demethylases driving lineage-specific epigenetic remodeling during B-cell development.26,121,231 Conditional knockout of Tet2/Tet3 impairs enhancer activity and disrupts peripheral B-cell lineage gene expression, resulting in defective B-cell differentiation and function (Fig. 3).27,232,233Fig. 3Full size imageKey epigenetic events orchestrating B-cell development, activation, and differentiation into effector and memory subsets. This figure illustrates stage-specific epigenetic mechanisms—including DNA methylation, histone modifications, RNA modifications, chromatin dynamics and ncRNAs—that govern B-cell fate decisions from early progenitors through effector and memory subsets. Early B-cell development: During the transition from pro-B to pre-B and immature B cells, epigenetic mechanisms play essential roles in lineage commitment and developmental progression. Combined loss of Tet2 and Tet3 arrests B-cell development at the pro-B-to-pre-B transition. The pioneer factor PU.1, with E2A, recruits Tet to the Igκ 3’ and distal enhancers; Tet-mediated demethylation then increases accessibility and drives Igκ germline transcription and rearrangement, and TET also sustains Irf4 expression, with Irf4 binding downstream. Without Tet, these enhancers remain methylated and inaccessible, and cells fail to reach the pre-B stage. CHD4, a remodeling ATPase associated with the NuRD complex, has three distinct functions: it is essential for early B-cell development (notably the pro-B to pre-B transition); in activated mature B cells, it directly binds H3K9me3 at the Igh locus to facilitate AID recruitment during CSR; and—independently—it represses Trp53 expression to support B-cell proliferation. Mettl14-mediated m6A deposition and Ythdf2-mediated recognition of m6A-modified transcripts regulate the large-to-small pre-B-cell transition. Usp22 facilitates c-NHEJ and supports γH2AX formation, and its loss impairs both V(D)J recombination (early B cells) and CSR (mature B cells); PP4 sustains γH2AX/NBS1 foci required for CSR; Sirt1 loss increases histone acetylation and activation-induced cytidine deaminase (AID). Naïve B cells and activation: Upon antigen encounter, naïve B cells undergo profound epigenetic reprogramming that facilitates activation and entry into differentiation pathways. H3/H4 acetylation correlates with germline transcript expression and AID activity. PP4 deficiency impairs class switch recombination (CSR). The lncRNA-CSRIgA, transcribed from ~2.6 Mb downstream of the Igh locus, is essential for CSR—particularly to IgA—while METTL3 catalyzes m6A modification of the Sμ germline transcript (SμGLT) and recruits the MPP6–YTHDC1 complex along with AID to promote CSR. At the histone modification level, Kmt2d deficiency impairs BCR/CD40 signaling, whereas Crebbp deficiency enhances and Ep300 deficiency impairs GC responses, indicating distinct functions. The IL-4/STAT6 pathway recruits the histone demethylase UTX to the Bcl6 enhancer to remove H3K27me3, with α-ketoglutarate (αKG) serving as an essential cofactor. TFH-derived signals induce KDM4A/KDM4C expression in B cells, reducing H3K9me3/me2 levels and cooperating with NF-κB p65 to regulate Cdkn2c/Cdkn3 expression, thereby modulating B-cell proliferation. Additionally, Lsd1 deficiency or NF-κB inhibition affects marginal zone B-cell (MZ B) development and regulates the fate balance between follicular B cells (FO B) and MZ B. Germinal center (GC) reaction: Within the GC microenvironment, B cells undergo somatic hypermutation (SHM), CSR, and affinity maturation—processes dependent on intense epigenetic remodeling. For m6A modifications, Ythdf2 regulates mRNA decay, while Igf2bp3 stabilizes Myc mRNA to maintain GC persistence. miRNAs, including miR-29b, miR-155, miR-181b, and miR-361, fine-tune Aicda expression. EZH2, as the catalytic subunit of PRC2, deposits H3K27me3 and cooperates functionally with BCL6 and the noncanonical PRC1–BCOR–CBX8 complex to promote GC B-cell differentiation. Tet2 and Tet3 enhance Aicda expression by depositing 5hmC at the Aicda superenhancer, thereby regulating CSR. For chromatin remodeling, partial Smarca4 loss leads to GC hyperplasia, while Smarca5 deficiency impairs B-cell activation, CSR, and antibody-secreting cell (ASC) differentiation. Memory B-cell (MBC) formation: MBCs are established and maintained through distinct epigenetic programs. EZH2 deficiency impairs CCR6 and CD73 expression in IgG+ MBCs. The transcription factor T-bet regulates chromatin accessibility in antiviral MBCs. miR-181 downregulation derepresses target genes, including RASSF6 and the transcription factor TOX, which contribute to the MBC transcriptional program. Plasma cell (PC) differentiation: Terminal differentiation into antibody-secreting PCs requires extensive epigenetic reprogramming. TET2/3 and vitamin C promote demethylation at Prdm1 loci. miR-23b, miR-30a, and miR-125b target the long 3’UTR of Prdm1 mRNA to negatively regulate Blimp-1 expression. For RNA modifications, Ythdf1 stabilizes Ighg1 transcripts and maintains IgG1 production in ASCs. The cBAF chromatin-remodeling complex (SMARCA2/4–ARID1A) co-localizes at ~90% of IRF4 binding sites, establishing the chromatin accessibility required for IRF4-driven PC differentiation. Figure created using Adobe Illustrator (Adobe Inc.)Following antigenic stimulation, GC B cells undergo global DNA hypomethylation relative to naïve B cells, with promoter regions of select genes becoming preferentially hypomethylated (Fig. 3). Activation-induced cytidine deaminase (AID, encoded by Aicda)-binding sites are overrepresented among hypomethylated loci.234 In a Dnmt1-hypomorphic model, impaired GC formation was associated with increased DNA damage, and differentially methylated genes were enriched in the NF-κB and MAPK pathways.234 AID-associated hypomethylation is impaired in TET2-deficient GC B cells, consistent with functional cooperation between AID- and TET-dependent demethylation pathways.235,236 Complementing AID function, TET2/3-mediated demethylation critically regulates chromatin accessibility and enhancer activity during B-cell activation;232,237 5hmC-marked regions show substantial overlap with open chromatin and active enhancers, with TET-responsive loci enriched for bZIP transcription factor binding motifs.238 A key functional target is the Aicda locus itself: TET2 and TET3 enhance CSR by upregulating Aicda,231,238 depositing 5hmC at two enhancer elements (TetE1 and TetE2) within the Aicda super-enhancer to promote demethylation and maintain chromatin accessibility.238 This TET recruitment depends on the bZIP transcription factor BATF, as BATF-deficient B cells show markedly reduced 5hmC deposition at TetE1,238 establishing BATF as a critical mediator of TET targeting to the Aicda enhancer.Differentiation of GC B cells into ASCs requires extensive transcriptional reprogramming, closely linked to DNA methylation reorganization.239 Approximately 10% of CpG sites become hypomethylated, with enrichment at enhancer regions; inhibition of DNA methylation enhances ASC commitment in a cell division-dependent manner, correlating with a fivefold increase in global mRNA transcription.239 During GC B cell-to-ASC differentiation, demethylation proceeds sequentially: first at NF-κB and AP-1 binding motifs, then at IRF and Oct-2 sites, coinciding with cell division-dependent activation and ASC commitment programs.239 Tet2/3 activity promotes ASC differentiation and is associated with induction of the Blimp-1 (encoded by Prdm1)/Xbp1/Irf4 program; ascorbic acid enhances this process through Tet2/3-dependent demethylation.240 Conversely, DNMT3A-mediated de novo methylation at E2A and PU.1–IRF composite binding motifs represses the PC chromatin state, limiting B-cell activation and PC differentiation.241DNA methylation also shapes other B-cell subsets. DNMT3A deficiency leads to selective expansion of B1a cells; genome-wide CpG methylation profiling has revealed that B1a development is driven by programmed demethylation at enhancers that remain methylated in B2 cells, thereby guiding B1 lineage commitment.242 In regulatory B cells (Bregs), demethylation at specific regulatory regions of the interleukin (IL)-10 locus defines distinct IL-10-producing states, characterizing Bregs as an epigenetically controlled functional B-cell subset.243Histone modificationsHistone acetylationThe balance between HATs and HDACs critically regulates B-cell development and function (Fig. 3). Dynamic changes in H3K27ac during B-cell development significantly impact gene expression programs.244 Among HATs, CREBBP and EP300 play distinct roles in GC B cells. Deletion of Crebbp in activated B cells enhances GC responses,245,246 consistent with its tumor suppressor function.246,247 In contrast, Ep300 deletion impairs GC responses, indicating nonredundant functions between these paralogs.248 At the molecular level, H3 acetylation at switch (S) regions correlates with germline transcript (GLT) expression, whereas H4 acetylation is associated with AID expression; H4 acetylation may serve as a chromatin marker for DNA damage repair during CSR.249,250HDACs also play essential roles in B-cell biology. B-cell-specific HDAC3 deficiency impairs GC reactions, with reduced DZ centroblasts and accumulation of LZ centrocytes.251 The NAD+-dependent class III HDAC Sirt1 is highly expressed in resting B cells but downregulated upon activation; its deficiency leads to increased Aicda expression through hyperacetylation of histone and nonhistone proteins at the Aicda promoter, establishing Sirt1 as a key epigenetic suppressor of AID during B-cell activation.252 The transcriptional repressor Blimp-1 interacts with HDACs to regulate histone acetylation and suppresses target genes such as c-Myc.253Histone methylation(1)H3K4 methylation as a key activating mark in B-cell developmentDuring early B-cell development, SETD1A-mediated H3K4 trimethylation is essential for the differentiation of progenitor cells into precursor B cells; Setd1a deletion blocks IgH gene rearrangement, thereby disrupting normal B-cell development.254 Upon entry into the GC stage, KMT2D (also known as MLL2)-catalyzed H3K4 mono-/di-methylation is required for proper GC B cell development and sustains a tumor-suppressive gene-expression program; conditional Kmt2d deletion causes widespread transcriptional dysregulation—enhancing proliferation while impairing terminal differentiation and CSR—and cooperates with antiapoptotic lesions (e.g., BCL2) to drive lymphomagenesis.255,256 This stage-specific requirement suggests that KMT2D exerts an indispensable tumor suppressor function during the GC stage. In contrast to these methyltransferases, the H3K4 demethylase LSD1 (KDM1A) directs B-cell fate by silencing enhancers associated with alternative lineages. It cooperates with Blimp-1 to drive plasmablast differentiation257 and with noncanonical NF-κB signaling to promote MZ B-cell development.258(2)H3K27 methylation and the repressive regulatory network in GC B cellsH3K27 trimethylation (H3K27me3) serves as a transcriptionally repressive epigenetic mark catalyzed by EZH2, the core catalytic subunit of PRC2.259,260 EZH2 is expressed in a subset of activated B cells, reaching its highest levels in GC B cells.261 Chromatin immunoprecipitation (ChIP)-based analyses and imaging studies have revealed that EZH2 regulates gene expression in GC B cells through bivalent chromatin structures, requiring site-specific binding of the transcriptional repressor BCL6 and involvement of the noncanonical PRC1 (ncPRC1)-BCOR-CBX8 complex (Fig. 3).262,263 At the functional level, EZH2 maintains the GC response by repressing CDKN1A expression,261,262 thereby promoting G1-to-S phase transition in GC B cells. In lupus-prone MRL/lpr mice, B-cell-specific Ezh2 deletion impairs plasmablast differentiation and is accompanied by reduced Xbp1 expression.264 EZH2 also governs the MBC compartment: Ezh2 deletion skews MBC differentiation toward a non-GC, IgM+ subset at the expense of class-switched, CCR6+ CD73+ MBCs, and the resulting Ezh2-deficient memory pool mounts impaired recall responses—forming fewer secondary GCs, antibody-secreting cells, and secondary MBCs upon heterologous viral challenge.265 The dynamic balance of H3K27 methylation also depends on precise regulation by demethylases. Upon IL-4 stimulation, STAT6 binds to the Bcl6 enhancer and recruits the H3K27me3 demethylase UTX, activating Bcl6 expression.266 IL-4-induced metabolic reprogramming further drives the accumulation of α-ketoglutarate—the obligate cofactor for UTX demethylase activity—reinforcing this regulatory axis.266 This interplay among metabolic reprogramming, signal transduction, and epigenetic modification cooperatively determines B-cell differentiation fate.(3)H3K9 methylation as an epigenetic bridge in T–B cell crosstalkBeyond H3K4 and H3K27 methylation, H3K9 methylation provides another layer of regulation for B-cell activation.26,267 Under in vitro TFH-mimicking stimulation, Kdm4a and Kdm4c are induced in B cells and are associated with a global reduction in H3K9me2/3.268 These demethylases synergize with NF-κB p65 to target WDR5, a member of the MLL complex, promoting the expression of the cell cycle inhibitors Cdkn2c and Cdkn3 and thereby calibrating the proliferation of activated B cells.268Histone phosphorylationHistone phosphorylation plays multifaceted roles in regulating B-cell function and development. γH2AX accumulates at IgH switch regions, where it facilitates long-range interswitch recombination by promoting DNA end-joining and preventing double-strand breaks from progressing to chromosomal breaks and translocations.269,270 γH2AX is essential for CSR but dispensable for SHM.269,271 Not only its accumulation but also its timely removal is tightly controlled: the phosphatase PP4 dephosphorylates γH2AX, and PP4 deficiency in mature B cells impairs ATR phosphorylation, leading to decreased retention of γH2AX-NBS1 complexes at DNA damage sites and consequently impaired CSR.272 H2B phosphorylation at Ser14 (H2B-Ser14P) accumulates during both SHM and CSR, but its presence in the absence of γH2AX distinguishes SHM from CSR—revealing that CSR and SHM, although both initiated by AID, engage distinct DNA damage response signatures.271Histone ubiquitinationHistone ubiquitination regulates B-cell DNA recombination through multiple mechanisms. H2B lysine 120 monoubiquitination (H2B-K120ub) is catalyzed by the RNF20/RNF40 heterodimeric E3 ligase and removed by the SAGA complex deubiquitinase USP22 in both early and mature B cells. RNF20 and RNF40 are required for DSB repair, and their deficiency impairs both homologous recombination (HR) and nonhomologous end joining (NHEJ)-mediated CSR.273 Conversely, Usp22 deficiency leads to H2B-K120ub accumulation, impairing γH2AX formation and the classical NHEJ (c-NHEJ) pathway; in early B cells, this results in blocked V(D)J recombination and developmental arrest at the pro-B-cell stage, whereas in mature B cells, it causes defective IgG/IgE CSR, while IgA CSR remains intact.274 H2A ubiquitination regulates CSR through the RNF8/RNF168 cascade: DNA double-strand breaks activate ATM kinase, which phosphorylates H2AX (γH2AX) and MDC1; MDC1 in turn recruits RNF8 to catalyze K63-linked polyubiquitin chains on chromatin substrates, which recruit RNF168 to mediate H2A K13/K15 monoubiquitination and stabilize 53BP1 accumulation at DSB sites.275,276 Knockdown of RNF8, RNF168, or 53BP1 in CH12F3-2 B cells significantly reduces CSR,275 and Rnf8-deficient mice exhibit impaired CSR and immunodeficiency.276Chromatin remodeling, accessibility, and associated epigenetic modificationsChromatin dynamics play a central role in B-cell development and function. In contrast to densely packed chromatin, open chromatin more readily recruits transcription factors to fulfill transcriptional demands during B-cell differentiation.277 Multiple chromatin remodeling complexes and transcription factors orchestrate this process through distinct yet complementary mechanisms.ATP-dependent chromatin remodeling complexesThe SWI/SNF complex is essential for B-cell proliferation and GC responses. SMARCA4 (Brg1) haploinsufficiency promotes GC hyperplasia with enhanced centroblast polarization.278 SMARCA4 acts as a haploinsufficient tumor suppressor that orchestrates GC dynamics by sustaining the activity of SPI1, the IRF family, and NF-κB—transcription factors that collectively antagonize BCL6. Consequently, partial loss of SMARCA4 weakens these signals and allows the BCL6-driven program to persist unchecked in centrocytes, skewing fate decisions toward dark-zone recycling and culminating in GC hyperplasia.278 The cBAF chromatin remodeling complex (SMARCA2/4–ARID1A) physically associates with IRF4 and colocalizes at approximately 90% of IRF4 binding sites on chromatin, establishing the chromatin accessibility essential for IRF4-mediated activation of PC transcriptional programs; accordingly, Arid1a deletion in B cells blocks PC differentiation.279 Separately, ARID1A loss instead redirects cell fate toward a pre-memory B cell state and predisposes to lymphomagenesis.280 More broadly, the ARID1A-containing cBAF complex also supports efficient GC responses by restraining inflammatory transcriptional programs.281The ISWI family, with SMARCA5 (SNF2H) as its core ATPase, has stage-specific functions in B-cell biology. During early development, SMARCA5 deletion arrests early B-cell development at the pro-B stage;282 in mature B cells, SMARCA5 is required for proliferation, CSR, GC formation, and ASC differentiation.283 Single-cell multi-omics studies have revealed that SMARCA5 promotes chromatin accessibility and transcriptional reprogramming at activation-related gene loci, facilitating transcription factor binding.283The NuRD complex integrates chromatin remodeling with histone deacetylation. It comprises the ATPase subunits CHD3/4, the histone deacetylases HDAC1/2, and either the methyl-CpG-binding protein MBD2 or the related subunit MBD3; together, these components execute diverse epigenetic regulatory functions.284 Chd4, as a core component of the NuRD complex, plays multiple roles in B-cell development, CSR, and proliferation. During early B-cell development, Chd4 deletion blocks the pro-B to pre-B-cell transition.285 In mature B cells, Chd4 regulates CSR: it directly recognizes the H3K9me3 mark at the Igh locus and mediates local chromatin remodeling to promote efficient AID targeting.285Chd4 deficiency results in suboptimal AID targeting and significantly reduced CSR efficiency.285 Furthermore, Chd4 regulates B-cell proliferation by maintaining transcriptional repression at the Trp53 locus—its deficiency relieves this repression, leading to p53 upregulation and consequently impaired B-cell proliferation.285 Another NuRD component, MTA2, regulates pre-B-cell gene expression through the HDAC1/2-dependent deacetylation activity of the NuRD complex—removing H3K27ac and other activating acetylation marks at lineage-specific loci—and functionally cooperates with AIOLOS/IKAROS and OCA-B to control lineage-specific transcription.286Transcription factors and chromatin accessibility dynamics in B-cell differentiationLineage-determining transcription factors work in concert with these remodeling complexes. EBF1 shapes B lymphocyte-specific epigenetic profiles by cooperating with RUNX1 in CpG demethylation and nucleosome remodeling287 and by relying on SWI/SNF activity to establish accessible chromatin for PAX5 binding.288 Subsequently, PAX5 activates approximately 170 B-cell-specific genes, including Cd19 and Cd79a, while E2A and EBF1 maintain the transcriptional program through H3K4 monomethylation at enhancers.289,290,291 During terminal differentiation, H3.3 is downregulated, relinquishing the B-cell-defining chromatin program that H3.3 actively sustains at the Pax5, Bcl6, and Bach2 loci; this disengagement permits chromatin reorganization toward PC-defining accessibility, licensing Irf4, Prdm1, and Xbp1 expression.292Recent ATAC-seq studies have further elucidated the molecular mechanisms underlying these chromatin dynamics. EBF1 acts as a pioneer factor through its C-terminal domain (CTD): the CTD harbors a prion-like domain (PLD) that undergoes liquid-liquid phase separation, enhanced by interaction with the RNA-binding protein FUS; these condensates recruit the chromatin remodeler Brg1 to open chromatin at B-lineage loci, thereby stabilizing EBF1 occupancy and licensing B-cell programming.293,294 Importantly, EBF1 activity is continuously required for maintaining local chromatin accessibility; acute EBF1 depletion leads to rapid loss of chromatin accessibility and deregulation of B-lineage genes.295 Notably, extensive epigenetic priming occurs in multipotent progenitors before B-lineage specification, with the majority of EBF1 and PAX5 binding sites already accessible in these progenitors.296 During GC reactions and terminal differentiation, B cells undergo dramatic chromatin reorganization. Approximately 28% of chromatin compartments change during B-cell maturation, characterized by widespread chromatin activation from naïve B to GC B cells and a reversal toward the naïve state upon MBC differentiation.28 However, this general pattern does not fully apply to antiviral MBCs, which retain distinct epigenetic signatures. Recent work demonstrates that antiviral MBCs progressively establish open chromatin at innate immune gene loci (Il6, Il27, Cxcl10, Irf1/7, Oas family) during GC differentiation, enabling enhanced innate immune transcription upon antigen re-encounter—a property that endows antiviral MBCs with trained-immunity-like features superimposed on classical antigen-specific memory.297 The transcription factor T-bet appears central to this process: antiviral MBCs acquire specific accessible regions at the Tbx21 locus, including the conserved CNS+6 element, that are absent in protein antigen-induced counterparts. Functionally, T-bet is required for antiviral MBC formation independent of its role in CSR, suggesting that it acts as an epigenetic regulator of GC-to-MBC fate decisions.297 Beyond these MBC-specific epigenetic features, division-coupled ATAC-seq profiling has identified a subset of genes with accessible but transcriptionally silent promoters marked by H3K27me3, including the essential PC transcription factor Blimp-1; EZH2 inhibition enhances PC formation by releasing this “poised” state.298 Furthermore, the histone acetyltransferase MOZ regulates GC fate decisions—its deficiency impairs dark-zone centroblast generation while altering MBC composition.299RNA modificationsThe m6A methylation machinery is critical throughout B-cell biology; in particular, the writer Mettl14 is required for early B-cell development.300 B-cell-specific deletion of either Mettl14 or Mettl3 severely impairs GC B-cell proliferation and antibody responses.301,302 At the molecular level, Mettl14-mediated m6A modifications, in a Ythdf2-dependent but Myc-independent manner, precisely regulate the expression of key genes governing positive selection and cell cycle progression in GC B cells.301 In particular, Mettl14 promotes the degradation of mRNAs encoding inhibitory regulators such as Lax1 and Tipe2, thereby relieving the repression of genes essential for positive selection and GC B-cell proliferation.301 Beyond GC maintenance, Mettl3-catalyzed m6A modification of the IgH locus-associated G-rich lncRNA SμGLT in B cells undergoing CSR recruits the MPP6–Ythdc1 complex, which subsequently brings AID and the RNA exosome complex to the SμGLT locus for 3’ end processing.303 This mechanism promotes efficient CSR while suppressing chromosomal translocations; inhibition of m6A modification at SμGLT or of Ythdc1 significantly reduces CSR efficiency and antibody diversity.303The functional outcomes of m6A modifications are primarily determined by distinct reader proteins that exert different effects on mRNA fate in GC B cells.302 Igf2bp3 stabilizes Myc mRNA and promotes MYC target gene expression, directly supporting B-cell proliferation.302 Ythdf2 independently regulates the oxidative phosphorylation gene expression program, forming a synergistic but mechanistically distinct network with Igf2bp3 to support core GC functions.302 Together, these two readers operate through independent regulatory axes—one promoting mRNA stability (Igf2bp3–Myc) and the other governing mRNA decay (Ythdf2)—to precisely coordinate GC B-cell function.302 Ythdf1 plays a central role in IgG antibody production: IgG heavy chain transcripts (Ighg) harbor m6A sites within their long 3’UTRs specifically recognized by Ythdf1.304 B-cell-specific Ythdf1 deficiency significantly impairs IgG production after antigen immunization by reducing Ighg1 mRNA abundance in IgG1-secreting cells (Fig. 3).304 Disrupting either the m6A modification of the nucleus-localized Ighg1 splicing intermediate or nuclear Ythdf1 localization reduces Ighg1 transcript stability,304 underscoring the indispensable role of the m6A machinery in sustaining antibody production.ncRNA regulation in B-cell development and functionmiRNAMicroRNAs (miRNAs) regulate multiple stages of B-cell development and function. The miR-17~92 gene cluster is essential for the pro-B to pre-B transition—its loss blocks this checkpoint and increases apoptosis.305 Premature overexpression of miR-150 or miR-34a also impedes B-cell development by downregulating c-MYB and FOXP1, respectively.306,307,308 In resting mature B cells, high miR-150 expression maintains homeostasis.306,307 Upon activation, miR-150 downregulation permits c-Myb upregulation, contributing to differentiation. Several miRNAs—including miR-155, miR-181b, miR-361, and miR-29b—fine-tune CSR and SHM by repressing AID.309,310,311 Additionally, miR-146a regulates CSR to IgA by targeting Smad2, Smad3, and Smad4 in the TGF-β signaling pathway; it is abundantly expressed in resting B cells but is downregulated upon activation.312 miRNAs also fine-tune TFH cell differentiation, a prerequisite for efficient GC reactions. Among positive regulators, miR-155 promotes TFH accumulation by inhibiting Fosl2 and Peli1,313 whereas miR-92a promotes human TFH precursor expansion through KLF2 and PTEN signaling in the context of type 1 diabetes (T1D) islet autoimmunity.314 Among negative regulators, miR-29a-3p targets ICOS in circulating TFH memory cells from patients with Graves’ disease, whereas miR-146a targets ICOS and participates in a negative feedback loop in TFH cells.315,316 The miR-17~92 cluster additionally coordinates TFH fate decisions.317 Following CSR, miR-181a/b expression is markedly reduced in IgG+ and IgA+ MBCs, leading to derepression of target genes, including RASSF6, TOX, TRERF1, TRPV3, and RORA—factors critical for MBC identity and survival.318 Additionally, miR-142 modulates Ras–ERK signaling to influence B-cell activation and Epstein‒Barr virus (EBV) reactivation.319miR-29 sustains mature B-cell survival and controls PC differentiation via the PTEN–PI3K pathway.320 The exceptionally long 3’UTR of Prdm1 mRNA (> 2,000 nt) makes Prdm1 expression particularly susceptible to miRNA-mediated regulation. Histone deacetylase inhibitors, such as valproic acid and butyrate, upregulate miR-23b, miR-30a, and miR-125b, which suppress Blimp-1 expression, and miR-155, miR-181b, and miR-361, which suppress AID expression; together, these effects inhibit CSR, SHM, and PC differentiation.321 In hypoxic GC microenvironments, miR-155 controls H3K36me2 levels by inhibiting Kdm2a, supporting oxidative phosphorylation and protecting high-affinity B-cell clones from ROS-induced apoptosis.322lncRNAAs key regulators, lncRNAs play critical regulatory roles in the immune system, particularly in B-cell-mediated adaptive immunity.323 High-throughput sequencing has identified 4,516 lncRNAs across 11 stages of B-cell development and activation, with the transcription factor PAX5 directly binding and regulating 109 of these in pro-B and mature B cells, and 184 in acute lymphoblastic leukemia cells.324 During early hematopoiesis, several nuclear lncRNAs influence lineage commitment. Knockdown of lncHSC-1 enhances myeloid differentiation at the expense of B-cell output, indicating a role in lineage allocation.325 Conversely, knockdown of lncHSC-2 increases peripheral T-cell numbers while reducing B-cell output, implicating it in HSC self-renewal and lymphoid lineage output.325 As B-cell development progresses, additional lncRNAs assume regulatory roles. For example, LncRNA00492 binds CTBP1 and promotes its ubiquitin-mediated degradation, thereby relieving CTBP1-mediated repression of Notch2 signaling and enabling MZ B-cell maturation.326 In female lymphocytes, the lncRNA Xist maintains XCI through heterochromatic modifications, including H3K27me3 and H2A-Ub.327 However, Xist RNA localization is lost from the inactive X at the pro-B stage, whereas heterochromatic marks persist in most pro-B cells and progressively diminish thereafter.327Upon B-cell activation, lncRNAs modulate signaling pathways and effector functions through multiple mechanisms. Overexpression of lncRNA 2900052N01Rik (also termed lnc-290) promotes LPS-induced activation via the NF-κB and ERK pathways, while its knockdown suppresses CD69/CD86 expression and diminishes proliferation, differentiation, and immunoglobulin production.328 Activated mature B cells restore Xist localization and heterochromatin through a YY1-dependent two-step mechanism; loss of Xist causes X-linked gene escape (e.g., TLR7) and drives CD11c+ atypical MBC differentiation.29,327,329 lncRNAs also regulate CSR. lncRNA-CSRIgA, located approximately 2.6 Mb downstream of the Igh locus, is important for efficient isotype-specific CSR, particularly IgA CSR.330 In MBCs, lncRNA profiles differ substantially from naïve B cells: class-switched IgG⁺ and IgA⁺ MBCs share a core mRNA-ncRNA signature, whereas unswitched MBCs retain a transitional transcriptome.318 Notably, several lncRNA loci cluster near the IgH region on chromosome 14, suggesting direct involvement in IgH regulation and antibody diversification. One such example is FAM30A, which is embedded within the IgH locus and transcribed in an antisense orientation relative to IgH gene segments.331 FAM30A expression positively correlates with both antibody responses and nearby immunoglobulin gene expression.331eRNAs, circRNAs, and ceRNAseRNAs are crucial regulators of B-cell functions, particularly in antibody diversification and CSR. Disruption of RNA exosomes leads to R-loop accumulation at eRNA loci, indicating that RNA exosomes normally help resolve DNA/RNA hybrids during these processes.332 Notably, lncRNA-CSR, an eRNA-like transcript that regulates the IgH 3’ regulatory region (3’RR) super-enhancer, is critical for CSR efficiency—its CRISPR-Cas9-mediated ablation impairs chromosomal looping and substantially reduces CSR.332 CircRNAs exhibit dynamic expression patterns throughout B-cell differentiation, suggesting stage-specific regulatory roles. ceRNA network analysis has identified candidate circRNA-miRNA-mRNA axes that may regulate BCR signaling (novel_circ_000317/000383-related axes involved in BCR signaling), complement receptor 2 expression (novel_circ_000150), and IL-4Rα expression (novel_circ_000701/000616 via miR-542-3p).333 In a five-participant pilot study, peripheral-blood circRNA profiles changed after BNT162b2 vaccination; comparison with single-cell datasets suggested that some differentially expressed circRNAs might originate from PCs.334Epigenetic dysregulation in humoral immunity-related diseases: mechanisms and therapeutic targetsB cells serve as key orchestrators of adaptive immunity, and their functional identity is shaped by epigenetic mechanisms that collectively govern B-cell lineage commitment, GC reactions, CSR, and immunological memory formation. Critically, disruption of these mechanisms underlies a broad spectrum of human diseases spanning four major domains of global health burden: in B-cell malignancies, epigenetic dysregulation has been most thoroughly characterized, driving the pathogenesis of highly prevalent B-cell lymphomas and leukemias; in metabolic and cardiovascular diseases, B-cell epigenetic alterations sustain chronic inflammation and metabolic dysfunction; in autoimmune diseases, multilayered epigenetic reprogramming dismantles immune tolerance, fueling autoantibody production and end-organ damage; and in infectious diseases, pathogens co-opt B-cell epigenetic machinery to establish persistent infection and immune evasion, while the host B-cell epigenome is continuously remodeled throughout infection and inflammation. This review systematically surveys the molecular architecture of B-cell epigenetic regulation across these four disease domains, delineates shared principles alongside disease-specific mechanisms, and identifies therapeutic targets.B-cell malignanciesB-cell malignancies—including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and B-cell acute lymphoblastic leukemia (B-ALL)—represent the disease context in which B-cell epigenetic dysregulation has been most thoroughly characterized. Across these entities, somatic mutations in epigenetic regulators converge with aberrant DNA methylation, disrupted histone modification, chromatin remodeling defects, and ncRNA dysregulation to drive oncogenic transcriptional programs, impair immune surveillance, and confer therapeutic resistance.DNA methylationThe dynamic regulation of cytosine methylation is orchestrated by AID-mediated deamination, DNMT1/UHRF1-dependent maintenance methylation, and TET-catalyzed oxidation of 5mC to 5hmC, collectively shaping B-cell epigenetic landscapes. AICDA overexpression accelerates GC-derived lymphomagenesis by driving epigenetic heterogeneity—predominantly at intronic and intergenic CpG sites—that is associated with enrichment of Myc, p53, Bcl6, GC-exit, and B-cell receptor signaling signatures.335 Loss of Tet2/3 in mature B cells leads to accumulation of unresolved G-quadruplex and R-loop structures, increased DNA damage, translocations at immunoglobulin switch regions, and spontaneous GC-derived B-cell lymphoma development; these defects are ameliorated by co-deletion of Dnmt1.336 Similarly, TET2 deficiency in GC B cells causes widespread hypermethylation of regulatory elements, including promoters and enhancers linked to CD40 signaling, antigen presentation, and GC exit, silencing key regulators, including Jarid2 and MHC class I components; these changes mirror hypermethylation patterns observed in TET2-mutant DLBCL (Fig. 4).236 In KMT2A/MLL-rearranged B-cell precursor ALL models, decitabine reduces LINE-1 and CDH13 methylation, induces cell cycle arrest and apoptosis, shows the strongest synergistic antiproliferative effects with cytarabine among tested cytostatic combinations, delays leukemic proliferation and reduces blast burden in xenograft and patient-derived xenograft models.337Fig. 4Full size imageEpigenetic dysregulation in B lymphocytes drives malignant transformation and immune evasion in B-cell malignancies. DNA methylation: In DLBCL, TET2 loss induces widespread promoter and enhancer hypermethylation, silencing CD40 signaling, antigen presentation, and GC exit genes. AICDA overexpression drives epigenetic heterogeneity, accelerating GC-derived lymphomagenesis. In CLL, disease-specific hypomethylation activates oncogenes (TCL1A, ZAP70, BTK) and immune checkpoint loci (CTLA-4, TIGIT), promoting disease progression. Histone modifications: The gain-of-function EZH2Y641 mutation deposits excess H3K27me3 at the SESTRIN1 locus, disabling mTORC1 inhibition and locking GC B cells in a self-renewing FL-like state. Loss-of-function mutations in CREBBP and EP300 reduce enhancer H3K27ac in DLBCL and FL, allowing the BCL6–SMRT–HDAC3 complex to silence antigen-presentation genes (CIITA, CD74) and CD40 signaling, enabling immune evasion; HDAC3 inhibition reactivates these programs and represents a dependency in CREBBP-mutant lymphoma. In TP53-mutant DLBCL, E2F1-driven SUV39H1 upregulation causes excessive H3K9me3 deposition at ERV loci, suppressing interferon signaling and reducing T-cell infiltration. Chromatin remodeling and 3D genome organization: ARID1A, a cBAF subunit, maintains chromatin accessibility at the RUNX3 promoter; ARID1A loss reduces RUNX3 expression, disrupts the RUNX3/ETS1 transcriptional complex that drives FAS expression, and thereby impairs FAS-mediated apoptosis in GC-derived B cells. Separately, lymphoma-associated MEF2B mutations can strengthen the interaction of this transcription factor with the cBAF ATPase SMARCA4. Super-enhancer (SE) rewiring drives oncogene activation through H3K27ac/MED1-enriched distal SEs that form aberrant chromatin loops across TAD boundaries, driving CCND2 overexpression in MM. In relapsed B-ALL, Hi-C profiling reveals B-to-A compartment switching at the JAK2 locus, increasing JAK2 expression to fuel leukemic proliferation. ncRNA regulation: miR-155 upregulates PD-L1 on tumor B cells, blocking CD8+ T-cell killing and promoting immune evasion. miR-130b suppresses IFNAR1/p-STAT1 signaling via the IFNAR1 3’UTR, reducing OX40L and promoting a Th17/IL-17–driven protumorigenic microenvironment; LNP-formulated anti-miR-130b is a candidate therapeutic. Downregulation of tumor-suppressive miR-15a/16-1, miR-29, and miR-181b derepresses BCL2 and TCL1A, driving CLL lymphomagenesis. Figure created using Adobe Illustrator (Adobe Inc.)The CLL and MM epigenomes are profoundly shaped by pervasive methylation remodeling at cis-regulatory domains and large-scale hypomethylated regions, driving aberrant chromatin states and transcriptional diversification. CLL is thought to derive from the naïve-to-memory B-cell maturation trajectory and recapitulates this distinct transcription factor (TF) programming order: NF-κB, OCT2, and IRF4 binding sites are demethylated earlier, whereas AP-1, EBF1, and RUNX3 sites are programmed later.30 This pattern contrasts with the NF-κB/AP-1-early and IRF/Oct-2-late order observed during normal ASC differentiation,239 reflecting divergent TF networks that govern memory versus effector B-cell fates, and is accompanied in CLL by de novo activation of regulatory elements marked by H3K4me1, H3K4me3, and H3K27ac.30,338 Cell-of-origin modeling further revealed that most CLL-specific CpGs (> 96%) are hypomethylated relative to the inferred cell of origin, with hypomethylated sites enriched in de novo super-enhancers and TF motifs including BATF, NFAT, and EGR1/2; affected super-enhancers harbor CLL-relevant genes such as CD5, IRF2, and CLLU1.339 In MM, genome-wide hypomethylation coexists with focal CpG island/transcription start site (TSS) hypermethylation and pronounced epigenetic heterogeneity, reflected by elevated elevated proportion of discordant reads (PDR), epipolymorphism, and epiallele switching, while stochastic methylation gains at bivalent/developmental promoters weaken the relationship between promoter methylation and gene expression.340 Functionally, CLL methylation programs are linked to differential expression of prognostic and immune-regulatory genes, including TCL1A, ZAP70, BTK, CD274, CTLA-4, TIGIT, CD276, and LILRB4,30,339 whereas in MM, partially methylated domain (PMD)-associated methylation instability contributes to transcriptomic variability, particularly in developmental and immune-related pathways, and is associated with H3K27me3 redistribution and three-dimensional (3D) genome alterations.340 Clinically, distinct CLL methylation-based programming subtypes—low-programmed (LP-CLL), intermediate-programmed (IP-CLL), and high-programmed (HP-CLL)—are associated with IGHV mutation status, transcriptional signatures, time to first treatment, and overall survival, while epigenetic heterogeneity metrics in MM show prognostic associations in a pilot cohort.30,340Histone modificationsHistone acetyltransferases CREBBP and EP300 coordinate enhancer-associated H3K27 acetylation to support GC B-cell transcriptional programs; CREBBP loss permits HDAC3-dependent enhancer deacetylation and transcriptional repression. CREBBP inactivation reduces approximately 17–20% of H3K27ac peaks, preferentially at enhancers, reinforcing BCL6–SMRT/NCOR–HDAC3-mediated silencing of GC-exit and immune-recognition programs, including CD40/IRF4 signaling and antigen-presentation genes such as CD74 and CIITA.247 EP300 and CREBBP regulate overlapping but partly distinct enhancer-associated programs: Ep300 deletion reduces dark-zone gene expression and GC B-cell numbers by approximately 50%, whereas Crebbp loss increases GC formation and alters the DZ/LZ balance, underscoring context-specific enhancer remodeling.248 These perturbations impair antigen presentation and PC differentiation; murine Crebbp-deficient lymphomas and human CREBBP-mutant FL/DLBCL accordingly show enrichment of BCL6–SMRT target repression and suppression of GC-exit programs.247,248 Selective HDAC3 inhibition or genetic ablation restores enhancer H3K27ac, reactivates MHC class II transcription, increases surface HLA-DR, and enhances T-cell stimulation in CREBBP-deficient contexts, revealing HDAC3 dependency in CREBBP-mutant lymphomas.247Extending the HDAC family’s therapeutic relevance beyond HDAC3, HDAC11 has emerged as a PC-selective vulnerability in multiple myeloma. The HDAC11-selective inhibitor elevenostat phenocopies Hdac11 loss by increasing IRF4 lysine 103 acetylation, impairing IRF4 nuclear localization and target-promoter binding, and inducing MM cell death; it also shows nanomolar ex vivo activity across MM patient specimens and synergizes with bortezomib.341 BET inhibitors, including JQ1, I-BET, and OTX015, reduce BRD4 binding at the MYC promoter, suppress MYC and BCL6 expression, and curtail proliferation in double-hit/triple-hit and MYC-expressing DLBCL models while reducing CD47 expression.342 BET inhibitors combined with vorinostat/SAHA enhance antiproliferative effects through p21 upregulation and histone acetylation, although their survival effect in double-hit/triple-hit lymphoma (DHL/THL) cells is limited; in contrast, BET inhibition combined with ABT-199 nearly abolishes cell survival and reduces BCL-XL and MCL-1.342 Finally, CREBBP-mutant DLBCL cells show heightened sensitivity to CREBBP/EP300 inhibitors CCS1477 and CU329, which induce G0/G1 arrest and deacetylation of H3K27 and H3K18, supporting therapeutic targeting of residual CREBBP/EP300 activity and EP300 dependency.248Beyond acetylation, repressive histone methylation—principally H3K27me3 and H3K9me3—constitutes a major oncogenic axis in B-cell malignancies. PRC2-mediated H3K27me3 deposition and its reversal by the demethylase UTX critically reshape B-cell epigenomes to drive lymphomagenesis. Mutant EZH2Y641 alleles enforce aberrant H3K27me3 at loci controlling GC recycling/TFH interaction, SESTRIN1–mTORC1 signaling, and tumor immunogenicity. Specifically, EZH2Y641F skews GC polarization by promoting slow expansion/accumulation of GC centrocytes while repressing Myc-dependent DZ recycling and genes required for TFH-dependent help, suppressing SHM and reducing clonal diversity toward a premalignant FL-like state;343 EZH2Y641X trimethylates the SESTRIN1 locus to disable mTORC1 inhibition, leading to unchecked 4E-BP1/S6 phosphorylation and accelerated lymphoma onset (Fig. 4).344 Loss of UTX elevates H3K27me3, downregulates B-cell differentiation factors (e.g., Dntt, Rag1), and upregulates Efnb1, fostering invasion, angiogenesis, and aggressive dissemination; notably, UTX-deficient lymphomas display heightened cytarabine sensitivity, suggesting a basis for epigenetically stratified chemotherapy.345 In models of acquired resistance, PRC2 component redistribution and reduced Uty expression produce sequential, stage-specific H3K27me3 changes at Tcf3/Spi1 (E2A/PU.1) target loci, establishing an epigenetic barrier that correlates with DNA hypermethylation and dedifferentiation.346 EZH2 inhibitors (MAK683, tazemetostat/EPZ6438, GSK126) erase these repressive marks through two complementary mechanisms: removal of H3K27me3 at BMP6/7 and ACVR1 loci unleashes SMAD1/5 activation and induces cell cycle arrest; blocking BMP–ACVR1 signaling instead abrogates PRC2 inhibitor efficacy, marking this pathway as essential for the response.347 Reactivation of antigen-presentation and costimulatory genes (Itgb7, Icam1, Cd86, and MHC class I/II related genes) augments CD8+ T-cell cytotoxicity, prolongs B cell–T cell immunological synapse duration, enhances CAR-T and bispecific antibody efficacy, and reduces T-cell exhaustion.348 Aberrant H3K9 methylation further shapes the immunological landscape of DLBCL: in TP53-mutated DLBCL, E2F1-driven upregulation of SUV39H1 leads to excessive H3K9me3 deposition at endogenous retroviral element (ERV) loci, silencing their transcripts, blunting interferon signaling, and reducing CD4+ and CD8+ T-cell recruitment;349 meanwhile, NCAPD3 reads H3K9me1 marks to recruit TFII-I to the SIRT1 promoter, enhancing SIRT1 expression and promoting DLBCL cell survival and proliferation.350In contrast to these repressive modifications, the dynamics of active histone methylation marks—shaped by LSD1-mediated H3K4 demethylation and SETD2-catalyzed H3K36 trimethylation—fine-tune GC B-cell differentiation, viral latency enforcement, and genomic integrity. The transcriptional repressor BCL6 recruits LSD1 to remove H3K4me1/2 at enhancers of terminal differentiation and apoptotic genes, thereby sustaining GC formation, proliferation, and affinity maturation.351 In EBV-infected Burkitt lymphoma B cells, LSD1 in complex with CoREST and ZNF217 demethylates H3K4 at genomic regions implicated in EBV lytic reactivation, reinforcing viral latency and limiting lytic reactivation352—a function convergent with the PRC1-dependent silencing of EBV lytic genes discussed in the following section. In a distinct oncogenic context, CLL cells exhibit upregulation of LSD1, which forms a complex with TCL1A that enhances the H3K4 demethylase activity of LSD1 and acts as an oncogenic transcriptional repressor of cell death and motility gene programs.353 In contrast, SETD2-mediated H3K36me3 is essential for DNA damage sensing in GC B cells: SETD2 haploinsufficiency reduces H3K36me3, impairs LEDGF recruitment and H4K16ac-marked chromatin integrity, diminishes γH2AX and CHK1 activation, and unleashes AID-driven off-target hypermutation that accelerates lymphomagenesis.354 Complementing this damage-sensing axis, H3S10 phosphorylation (H3S10ph) marks mitotic entry and exhibits distinct kinetics between reactive GC B cells and lymphoma cells: whereas physiological G2/M checkpoint control governs normal cell cycle progression in reactive GCs, lymphoma cells display accelerated G2/M transition and elevated mitotic rates attributable to impaired checkpoint function and defective DNA repair.355 Together, the essential role of LSD1 in BCL6-driven lymphomagenesis, SETD2-mediated suppression of oncogenic hypermutation, and H3S10ph-linked mitotic dysregulation highlight active histone modification dynamics as equally consequential—and functionally divergent—determinants of GC B-cell transformation.Chromatin remodeling and 3D genome organizationARID1A, a subunit of the cBAF remodeling complex, is required for FAS-dependent immune surveillance in GC-derived B cells: its loss reduces RUNX3 promoter accessibility and expression, disrupting the RUNX3/ETS1 co-transcriptional complex that drives FAS expression and thereby impairing FAS-mediated apoptosis (Fig. 4).356 In addition, MEF2B C-terminal mutations stabilize a hyperactive MEF2B by strengthening its interaction with the SWI/SNF ATPase SMARCA4 while escaping CUL3/KLHL12-mediated ubiquitination, driving aberrant target-gene activation and GC-derived B-cell lymphomagenesis.357Beyond nucleosome remodeling, integrative ATAC-seq, Hi-C, and chromatin profiling studies converge on a paradigm in which chromatin accessibility, 3D genome architecture, and super-enhancer (SE) remodeling cooperatively reprogram transcriptional landscapes across B-cell malignancy subtypes, consistently linking aberrant cis-regulatory activation to oncogene overexpression and immune evasion. In pediatric B-ALL, approximately 252,000 accessible chromatin regions (ACRs) gain accessibility relative to normal pre-pro/pro-B progenitors, enriched at the promoters of oncogenes such as IL7R, TCL1A and TCF3 and at the MYC blood enhancer cluster (BENC) SE.358 Strikingly, more than half of the ACRs identified across the cohort fall in “quiescent” regions (i.e., regions without well-defined histone marks) that nonetheless acquire H3K27ac and support active transcription in B-ALL.358 Enhancer activity is also highly dynamic during disease evolution: onset and relapse samples harbor at least tenfold more differentially active cis-regulatory elements (CREs) than expected by chance.359 Among these, 11,083 highly penetrant, clonally shifting regulatory sites—approximately 90% of them distal and bound by EBF1, ETS1, ERG and RUNX factors—produce eRNAs that functionally sustain oncogenes, with MYB and DCTD validated as direct targets.359 Complementary Hi-C profiling reveals recurrent 3D genome remodeling in relapsed B-ALL, including A/B compartment and TAD-interactivity changes at loci such as JAK2 and a recurrent loss of TAD interactivity at PCDH9.360 At regions of stable accessibility, differential H3K27ac enhancer–promoter looping emerges at relapse—exemplified by increased looping at FLT1—converging on candidate drivers of clonal evolution and glucocorticoid resistance, with MN1 and ATXN1 functionally validated and FLT1 nominated as a relapse-associated target.360In mature B-cell malignancies, analogous cis-regulatory rewiring underlies subtype identity and progression. In CLL, IGHV mutation status dictates thousands of differential regulatory regions: IGHV-mutated CLL (mCLL)-specific enhancers are enriched for BATF/BCL6 binding and H3K27ac/H3K4me1 marks, whereas IGHV-unmutated CLL (uCLL) displays CTCF/RAD21-occupied sites and divergent BCR signaling networks; chromatin state hidden Markov model (chromHMM) analysis further reveals activation of latent enhancers and conversion of poised promoters to H3K27me3-repressed states.338,361 In MM, an H3K27ac/MED1-marked SE drives CCND2 expression via MAF binding.362 In FL progressing to double-hit lymphoma, AID/APOBEC-driven kataegis targets H3K27ac-rich SEs, exemplified by PAX5-TSS2 mutations that redirect chromatin loops to a ZCCHC7 SE and trigger global translational reprogramming.363 In GC B-cell lymphomas, concurrent CREBBP and KMT2D loss disrupts SE integrity to repress NF-κB/BCR/IL-4 signaling and immune synapse genes, accelerating lymphomagenesis and impairing CD8+ T-cell responses.364Therapeutically, CRISPR-mediated SE perturbation at CCND2, MYB and DCTD impairs malignant growth,359,362 whereas restoring CREBBP/KMT2D activity364 or targeting the AID–APOBEC axis363 holds promise for sensitizing tumors to immunotherapy.RNA modificationsIn B-cell malignancies, the dual m5C/m6A reader YTHDF2 is overexpressed—most consistently in B-ALL—and couples energy supply to immune escape: as an m5C reader, it stabilizes ATP synthase mRNAs to sustain ATP synthesis, whereas as an m6A reader, it destabilizes CD19 and HLA-DM transcripts to drive antigen escape.365 Its inhibitor CCI-38 suppresses aggressive B-cell malignancies and sensitizes them to CAR-T therapy.365 In CLL, a high abundance of the m6A writer METTL3 drives splicing factor protein expression through m6A-dependent translational control (ribosome recycling and decoding), promoting aberrant splicing and aggressive disease and marking METTL3 as a therapeutic vulnerability.366 Beyond m6A, additional RNA modifications—including m5C and Ψ—are increasingly implicated in B-cell malignancy biology, although their mechanistic characterization remains nascent. In DLBCL, NSUN2-mediated m5C modification stabilizes CD274 (PD-L1) mRNA through a YBX1-dependent mechanism, promoting tumor immune evasion and M2 macrophage polarization.367 In MM, the same NSUN2/YBX1 axis deposits m5C on lncRNA MALAT1, enhancing its stability and facilitating its exosomal export to osteoclasts, where it drives receptor activator of NF-κB ligand (RANKL)-mediated bone destruction.368 For Ψ, polysome profiling of CLL B cells has identified a “ribosome-related” transcriptomic signature characterized by reduced polysomal loading of mRNAs encoding DKC1 (dyskerin), the catalytic component of H/ACA ribonucleoprotein complexes responsible for pseudouridylation; patients with low dyskerin expression exhibit significantly shorter overall survival.369 Together, these findings highlight the functional breadth of epitranscriptomic regulation in B-cell malignancies and underscore the need for systematic interrogation of RNA modification pathways.ncRNA regulationncRNAs in B-cell malignancies modulate key immunoregulatory and prosurvival circuits by targeting immune checkpoint molecules, antiapoptotic regulators, and oncogenic signaling pathways. In DLBCL, miR-155 upregulates CD274 (PD-L1) expression in DLBCL cells; the resulting PD-1/PD-L1 interaction both induces Fas-mediated CD8+ T-cell apoptosis and suppresses CD8+ T-cell function through AKT and ERK dephosphorylation (Fig. 4).370 In parallel, miR-130b targets the IFNAR1 3’UTR to suppress IFNAR1/pSTAT1 signaling, reducing OX40L expression and promoting Th17 cell recruitment through altered OX40/OX40L signaling, thereby elevating IL-17 secretion and fostering a protumorigenic Th17 microenvironment (Fig. 4).371 In B-cell precursor acute lymphoblastic leukemia (B-ALL), subtype-specific lncRNAs—including PVT1 and GAS5 in DUX4-rearranged (DUX4-like) subtypes and EGOT in Philadelphia chromosome-like (Ph-like) subtypes—are stably expressed from diagnosis through relapse, exhibit inverse correlations between promoter methylation and expression, and are co-expressed with genes in the TGF-β, Hippo, p53, JAK-STAT, PI3K-AKT, and NF-κB pathways.372 Additionally, downregulation of the tumor-suppressive miRNAs miR-15a/16-1, miR-29, and miR-181b unleashes BCL2 and TCL1A overexpression in CLL, driving malignant B-cell proliferation and survival.373 Beyond individual miRNA–target axes, ceRNA networks constitute an additional regulatory layer: in DLBCL, SMAD5-AS1 sponges miR-135b-5p,374 and circEAF2 (derived from EAF2) sequesters EBV-encoded miR-BART19-3p,375 each derepressing APC to suppress Wnt/β-catenin-driven proliferation.Clinically, the miR-155 axis is both prognostic and actionable: elevated miR-155 predicts poorer survival and reduced CD8⁺ T-cell responses in DLBCL, and PD-1/PD-L1 blockade reverses miR-155-mediated T-cell apoptosis while restoring AKT/ERK activation.370 Similarly, elevated miR-130b correlates with relapse and inferior survival via a protumorigenic Th17 microenvironment, and OX40 agonists combined with lipid-nanoparticle-delivered anti-miR-130b oligonucleotides reverse this axis, restrain Th17 accumulation, re-engage autophagy (LC3B upregulation and p62 downregulation), and suppress tumor growth with minimal toxicity.371 In B-ALL, relapse-associated lncRNA methylation patterns further mark treatment-refractory disease.372 Together, these findings highlight the multilayered contribution of miRNA, lncRNA, and circRNA networks to oncogenic transcriptional control and immune evasion across B-cell malignancy subtypes.Metabolic and cardiovascular diseasesWhile the epigenetic alterations described above are driven by somatic mutations and clonal selection within malignant B-cell populations, a distinct category of B-cell epigenetic dysregulation arises from chronic metabolic and environmental stress—without requiring genomic mutations—yet engages the same chromatin machinery to sustain pathological inflammation. Metabolic diseases, including obesity, T1D, type 2 diabetes (T2D), gestational diabetes mellitus (GDM), and atherosclerosis, are increasingly recognized as conditions in which B-cell epigenetic reprogramming drives chronic immune-metabolic dysfunction, with hyperglycemia, hyperlipidemia, inflammatory cytokines, and metabolic intermediates producing lasting alterations in B-cell gene expression and immune output.DNA methylationIndividuals with obesity exhibit a significant global increase in B-cell DNA methylation, a change also observed in NK cells of T2D patients but not in T-cell subsets, suggesting selective engagement of methylation machinery in B cells and NK cells.376 In T2D B cells, the cytosine at position −235 relative to the UBASH3A transcription start site is moderately hypermethylated, implying locus-specific regulation that may alter ubiquitin-mediated immune signaling. Functionally, elevated B-cell methylation correlates with insulin resistance (measured by the homeostatic model assessment of insulin resistance, HOMA-IR) (Fig. 5).376 Extending this cell-type-specific view to cardiovascular disease, cell-sorted analyses in atherosclerosis reveal B-cell–resolved methylation changes: CD19⁺ B cells from ischemic-stroke/atherosclerosis patients show intermediate promoter methylation of ALOX12 and AIRE1—higher than in monocytes but lower than in T cells—implicating cell-type-specific DNA methylation in the inflammatory mechanism of atherosclerosis (Fig. 5).377 In the context of GDM, a cell-type-deconvoluted cord blood epigenome-wide association study (EWAS) identified B-cell–specific differentially methylated CpGs—including loci annotated to LDLR, SCARF1, and SORL1—that were collectively enriched in the low-density lipoprotein (LDL) transport Gene Ontology pathway;378 whether these methylation differences functionally affect lipoprotein handling in offspring requires further validation (Fig. 5). Notably, this cell type-resolved analysis also reveals divergent methylation–body mass index (BMI) associations in CD8+ T cells and monocytes, underscoring the contribution of immune cell heterogeneity to early childhood metabolic trajectories.378Fig. 5Full size imageB-cell epigenetic reprogramming in metabolic disease. DNA methylation: In T2D and obesity, CD19+ B cells exhibit global hypermethylation—not observed in the analyzed T-cell subsets—that correlates with insulin resistance (HOMA-IR); concurrent UBASH3A promoter hypermethylation may silence ubiquitin signaling and amplify BCR activation. A cell-type-deconvoluted EWAS of cord blood identified B-cell-specific differentially methylated CpGs enriched in a low-density lipoprotein (LDL) transport Gene Ontology pathway; representative genes annotated to this pathway (LDLR, SCARF1, SORL1) are shown. In atherosclerosis, cell-sorted analyses reveal B-cell–resolved epigenetic changes: CD19⁺ B cells from ischemic-stroke/atherosclerosis patients show intermediate promoter methylation of ALOX12 and AIRE1—higher than in monocytes but lower than in T cells. Histone modifications: In atherosclerosis, proinflammatory cytokines enhance p300 recruitment to the miR-19a promoter, driving H3 acetylation and miR-19a upregulation that suppresses IL-10 production in peripheral B cells, promoting a proinflammatory phenotype; the p300 inhibitor garcinol reverses this effect. miRNA regulation: In peripheral B cells from patients with diabetes, TNF-α induces miR-550a, which is associated with HDAC1 and EGR1 occupancy at the CYP27B1 promoter and reduced 1α-hydroxylase expression; miR-550a inhibition, HDAC inhibition, or EGR1 knockdown reverses CYP27B1 repression in the experimental system. In NOD mice, miR-34a overexpression targets Foxp1 to block early B lymphopoiesis, reducing pro-B and pre-B cells 2–5-fold and marginal zone B cells (MZ B) ~33-fold, impairing autoantigen presentation to CD4+ T cells and conferring resistance to T1D. Figure created using Adobe Illustrator (Adobe Inc.)Histone modifications and miRNA regulationHistone modifications and chromatin remodeling in B cells orchestrate immune activation and metabolic dysregulation in both atherosclerosis and diabetes. In peripheral CD19⁺ B cells, atherosclerosis-associated cytokines (TNF-α, IFN-γ and IL-4) drive p300-mediated histone H3 acetylation at the miR-19a promoter, upregulating miR-19a to suppress IL-10; p300 inhibition with garcinol reverses this cytokine-induced IL-10 loss.379 In diabetic B cells, TNF-α upregulates miR-550a, which indirectly permits HDAC1 and EGR1 co-occupancy at the CYP27B1 promoter, leading to chromatin remodeling and decreased 1α-hydroxylase expression (Fig. 5).380 Therapeutically, the p300 inhibitor garcinol blocks cytokine-induced miR-19a elevation and restores IL-10 levels;379 HDAC inhibition with trichostatin A or EGR1 knockdown reverses miR-550a-mediated CYP27B1 repression.380 Beyond these specific epigenetic circuits, B cells exert both atheroprotective and proatherogenic functions in atherosclerosis,381 underscoring that such chromatin-level regulation operates within a functionally heterogeneous B-cell compartment.This heterogeneity is shaped in part during B-cell development, where miR-34a acts as a developmental regulator linking B-cell lymphopoiesis to T1D pathogenesis. miR-34a overexpression within the B10 insulin-dependent diabetes resistance locus 9.3 (Idd9.3) of nonobese diabetic (NOD) mice disrupts early B-cell lymphopoiesis by targeting Foxp1, leading to a 2–3-fold reduction in pro-B and pre-B cells and a marked loss of MZ B cells; these developmental deficits impair peripheral B-cell compartments and suppress autoantigen presentation to CD4+ T cells (Fig. 5).382 In NOD.B10 Idd9.3 mice, miR-34a-mediated Foxp1 depletion diminishes pancreatic lymph node T-cell proliferation and confers resistance to T1D onset.382 Enhancing miR-34a activity or suppressing Foxp1 to curtail autoreactive B-cell priming may therefore represent a strategy to enhance immune tolerance and prevent T1D.Autoimmune diseasesBeyond metabolically induced epigenetic drift, B cells can also undergo coordinated, antigen-driven epigenetic reprogramming that dismantles self-tolerance—a process most thoroughly characterized in the major autoimmune diseases. Epigenetic dysregulation is also increasingly recognized in other systemic autoimmune diseases, such as systemic sclerosis (SSc)—a rare but aggressive connective-tissue disease marked by vasculopathy, fibrosis, and disease-specific autoantibodies—where aberrant DNA methylation, histone modifications, and noncoding RNAs contribute to pathogenesis and represent potential therapeutic targets.383DNA methylationDNA methylation represents the most extensively studied layer of epigenetic regulation in B cells across autoimmune diseases, with systematic dysregulation thoroughly documented in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjögren’s syndrome (pSS), and multiple sclerosis (MS)—spanning from foundational mechanistic discoveries to clinical phenotypes.Foundational insights into DNA methylation dysregulation in SLE were established by the seminal work of Bruce Richardson’s group in the 1990s and early 2000s: genome-wide reduction in DNA methylation levels384 led to aberrant overexpression of methylation-sensitive genes (ITGAL385 and CD70386); adoptive transfer of 5-azacytidine (5-azaC)-treated CD4+ T cells into syngeneic mice was sufficient to induce lupus-like autoimmunity,387 establishing hypomethylation as a causal driver—rather than merely a consequence—of lupus pathogenesis. At the B-cell level, Tet2/Tet3-deficient B cells fail to downregulate the costimulatory molecule CD86 following chronic antigen stimulation, leading to T-cell hyperactivation and autoantibody production;388 Tet2 and Tet3 suppress Cd86 expression through HDAC-dependent mechanisms and demethylation at the Cd86 intronic region,388 with TET3 additionally identified as an SLE susceptibility gene by genome-wide association studies (GWAS) (Fig. 6).389 At the genome-wide level, SLE B-cell epigenetic remodeling follows differentiation stage-dependent patterns: CpG methylation at super-enhancer regions progressively decreases along the resting naïve (rN) to switched memory (SM) trajectory (Fig. 6);31 transitional B cells exhibit the strongest diagnostic methylation signature, with 60 of approximately 460,000 CpG sites reaching genome-wide significance and remarkable diagnostic accuracy, while African American patients display more pronounced hypomethylation at EBF1 binding sites in transitional B cells;390 promoter hypermethylation affects 1,628 genes in SLE B cells,391 and hypomethylation of interferon-regulated genes (IFI44L, PARP9, and IFITM1) is shared across multiple immune cell lineages.391Fig. 6Full size imageAberrant epigenetic modifications in B lymphocytes drive autoimmunity in SLE and RA. Top panel: Epigenetic alterations in B cells from patients with SLE or from mouse models of SLE. The body schematic summarizes the multi-organ clinical spectrum of SLE, distinguishing major organ involvement (red: kidney, blood) from minor organ involvement (blue: skin, joints), together with the hallmark malar (butterfly) rash. DNA methylation and demethylation: PBMCs from SLE patients exhibit genome-wide hypomethylation accompanied by DNMT1 downregulation and TET2 upregulation. In B cells, 1,628 genes harbor differentially methylated CpG sites, with interferon-regulated genes showing pronounced hypomethylation. In contrast to other cell types, differentially methylated CpG sites in B cells are predominantly hypermethylated, with the most significant upstream regulators including TNF and EP300. During B-cell differentiation from resting naïve B cells to MBCs, super-enhancer regions undergo progressive demethylation. TET2/3 suppress CD86 expression in autoreactive B cells through HDAC-dependent mechanisms and DNA demethylation at promoter and intronic regions, thereby maintaining B-cell tolerance; notably, TET3 has been identified as an SLE susceptibility gene through GWAS. Histone modifications: The selective HDAC6 inhibitor ACY-738 exerts therapeutic effects in lupus mouse models by suppressing BCR signaling, reducing GC formation, and blocking plasma cell (PC) differentiation. In B cells from SLE patients, enhanced AICDA expression correlates negatively with SIRT1 expression. Reduced SIRT1 expression in SLE B cells releases its repression of AICDA, leading to increased production of autoantibodies, including anti-dsDNA, anti-histone, and anti-ribonucleoprotein antibodies. JMJD3 is upregulated in B cells from SLE patients, leading to transcriptional activation of its target genes. GSK-J4 inhibits JMJD3 activity, thereby blocking the aberrant differentiation of naïve B cells into PCs and classical memory B cells (CMBs) in SLE patients and reducing autoantibody production. Chromatin accessibility: In resting-naïve (rN) B cells from patients with SLE, loci encoding immune and transcriptional regulators—IFI44, STAT4, FOSL2, NR4A1, NR4A3 and SPRY2—display increased chromatin accessibility and expression relative to healthy controls, indicating that an epigenetic disease program is established before overt B-cell activation. In pathogenic double-negative 2 (DN2) B cells, the accessible chromatin landscape is programmed predominantly by T-bet (TBX21), AP-1 (JUN, ATF3), IRF9 (ISGF3) and EGR family transcription factors, with ATF3 reaching maximal expression and peak motif accessibility in SLE DN2 cells. Upward arrows denote upregulation. RNA modifications: In antibody-secreting cells (ASCs) from SLE patients, upregulated YTHDF1 expression promotes the formation of nuclear RNA foci containing IGHG1 mRNA and is associated with increased autoantibody titers. In B cells from SLE patients, the tRNA m7G modification “writer” METTL1 and its cofactor WDR4 are upregulated, catalyzing increased m7G modification of specific tRNAs, thereby preferentially translating BCR signaling pathway-related proteins, enhancing BCR signal transduction, and ultimately promoting autoantibody production and SLE disease progression. Long noncoding RNA (lncRNA) XIST: B-cell-specific disruption of the XIST ribonucleoprotein complex can weaken silencing and permit escape of selected X-linked immune genes, including TLR7; in experimental models, Xist loss together with TLR7 stimulation promotes the expansion of CD11c⁺ atypical memory B cells (ABCs). Bottom panel: Epigenetic alterations in B cells from patients with RA or from mouse models of RA. The body schematic summarizes the predominantly articular involvement of RA—affecting the synovium, cartilage, and joints of the hands and feet, together with C1-C2 (atlantoaxial) erosion—all shown as major joint involvement. DNA methylation and demethylation: In B cells from early RA patients, 2,238 CpG sites exhibit differential methylation involving 1,362 genes, with approximately 60% displaying hypermethylation. Among these, 113 CpG sites constitute a B-cell-specific methylation signature capable of completely distinguishing all RA patients from healthy controls. Additionally, an epigenome-wide analysis of RA B cells identified 64 differentially methylated CpG sites relative to healthy controls; among the loci most strongly associated with RA, CD1C-associated sites were hypermethylated, whereas TNFSF10-associated sites were hypomethylated. In contrast, DNA demethylation by 5-azacytidine (a DNMT inhibitor) activates the aryl hydrocarbon receptor (Ahr) and lowers Aicda, reducing CSR, GC formation and IgG1 production to alleviate arthritis. Non-histone substrate modification: Jmjd1c demethylates the non-histone substrate Stat3 at Lys140, promoting Ptpn6-mediated Stat3 dephosphorylation and inactivation, thereby suppressing PC differentiation. Jmjd1c deficiency leads to sustained STAT3 activation, excessive PC generation, and RA exacerbation. MicroRNA regulation: Small RNA sequencing reveals 27 differentially expressed miRNAs (including miR-223-3p and miR-486-3p) in CD19+ B cells from MTX-treated RA patients in remission, targeting key B-cell developmental genes such as PRDM1 and PTEN. miR-155 exhibits a pro-pathogenic mechanism: it is highly expressed in CD19⁺ B cells from RA patients (particularly in IgD⁻CD27⁻ MBCs from ACPA-positive patients) and suppresses PU.1 expression; experimental inhibition of miR-155 restores PU.1 expression and reduces antibody production. miR-29a supports GC B-cell proliferation and antibody production; miR-29a deficiency confers near-complete protection from collagen-induced arthritis (CIA) in mice. Figure created using Adobe Illustrator (Adobe Inc.)The causal link between DNA hypomethylation and autoimmunity established in SLE was directly extended to therapeutic investigations of RA. In the proteoglycan-induced arthritis (PGIA) mouse model, 5-azaC restores aryl hydrocarbon receptor (Ahr) expression in B cells by demethylating the hypermethylated Ahr promoter.392 Ahr reactivation then suppresses Aicda transcription, diminishing AID expression, impairing CSR and GC B-cell function, and ultimately reducing IgG1 production and GC B-cell numbers (Fig. 6).392 These combined effects decrease autoantibody production and improve arthritis scores in murine models.392 In humans, a genome-wide methylome study of treatment-naïve early RA identified 2238 differentially methylated CpGs across 1362 genes (~ 60% hypermethylated) and a 113-CpG B-lymphocyte signature distinguishing patients from controls;393 a separate B-cell EWAS pinpointed CD1C (hypermethylated) and TNFSF10 (hypomethylated) as the loci most strongly associated with RA risk.394The experimental findings in RA demonstrated that targeted DNA methylation intervention can operate through disease-relevant pathways—a principle subsequently validated in pSS. In pSS, B-cell methylome remodeling is more extensive, with aberrant patterns closely intertwined with genetic susceptibility loci. Miceli-Richard et al. identified 6707 differentially methylated CpG sites (affecting 3619 genes) in peripheral blood CD19+ B cells from patients, with 44% showing hypomethylation and DNA methylation patterns significantly overlapping with genetic susceptibility loci, suggesting interplay between genetic and epigenetic dysregulation.395 Imgenberg-Kreuz et al. identified 453 differentially methylated sites in CD19+ B cells, with interferon-regulated genes (MX1, IFI44L, and PARP9) showing marked hypomethylation that inversely correlates with their expression levels (IFI44L mRNA upregulated in hypomethylated patients).396 Beyond B-cell-intrinsic changes, B-cell infiltration induces DNA demethylation in salivary gland epithelial cells via PKCδ/ERK-mediated suppression of DNMT1,397 directly linking B-cell-mediated inflammation to epigenetic remodeling in target tissues. Critically, these methylation aberrations are not independent of genetic background: methylation quantitative trait loci (meQTLs) at known pSS risk loci—most notably the rs4728142 variant in the IRF5–TNPO3 region, associated with cg04864179 methylation—together with genetic–epigenetic interactions across the HLA region, indicate that DNA methylation in pSS is partly under genetic control.396 Clinically, the extent of this epigenetic dysregulation correlates with disease activity,395 and the most pronounced hypomethylation of interferon pathway genes is observed in anti-SSA/SSB antibody-positive patients.395,396Hypomethylation of interferon-regulated genes also represents a central feature of MS B-cell epigenetic dysregulation. B cells are the most epigenetically altered immune cell type in peripheral blood in MS, with global DNA hypomethylation constituting their core epigenetic signature: genome-wide bisulfite sequencing of treatment-naïve, first-episode patients identified 4933 MS-associated differentially methylated regions in B cells—more than in monocytes or T cells—enriched for genes governing B-cell differentiation and activation.398 At the cell-subset level, pathogenic ABCs enriched in MS patients show characteristic hypomethylation at CXCR3, ITGAX, IRF5, BTK, and the lineage-defining factors TBX21 (T-bet) and STAT1,399 an epigenetic signature consistent with their meningeal infiltration and hyperreactive engagement of autoreactive T cells.399TBX21 hypomethylation is associated with increased T-bet expression and acquisition of a T-bet⁺ CXCR3⁺ phenotype that may enhance IFN-γ–dependent crosstalk with Th1 cells and reinforce CNS inflammation;399,400 consistent with this, T-bet⁺ CXCR3⁺ B cells are enriched in inflamed brain and meningeal tissue of progressive MS relative to peripheral blood.399,400 In a subset of secondary progressive MS (SPMS) cases, meningeal ectopic lymphoid follicles with GC-like features are associated with earlier onset, more severe cortical pathology, and accelerated disability,401 and these B cells may contribute to follicle formation and maintenance through sustained B–T cell interactions.399 Together, these findings suggest a model linking ABC DNA-methylation changes, T-bet-driven phenotype acquisition, and ectopic lymphoid structures in MS, although a direct causal chain from hypomethylation to follicle formation remains to be established.Histone modificationsWhereas DNA methylation establishes the foundational layer of B-cell epigenetic regulation, histone modifications further shape gene expression states; their dysregulation in SLE, RA, and pSS holds equally broad pathogenic significance and has emerged as a critical target for therapeutic intervention.In SLE B cells, histone methylation imbalance represents a central mechanism driving aberrant differentiation. Elevated EZH2 directly binds the BACH2 promoter, depositing H3K27me3 and suppressing BACH2 expression, leading to excessive B-cell differentiation into plasmablasts; EZH2 expression positively correlates with anti-dsDNA antibody titers and disease activity (Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group index scores, abbreviated as SLEDAI and BILAG).402 Complementing this EZH2-mediated methylation excess, dysregulation of demethylases further exacerbates the epigenetic imbalance: KDM4A and KDM4C are significantly downregulated in both resting and activated SLE B cells, resulting in impaired H3K9me2/me3 demethylation upon activation, thereby disrupting the downstream KDM4-NF-κB-WDR5-CDKN2C/3 axis that normally restrains B-cell proliferation.268 In contrast, JMJD3 is overexpressed in SLE B cells, specifically promoting naïve B-cell differentiation into CD27+ MBCs,403 with the selective JMJD3 inhibitor GSK-J4 effectively suppressing this aberrant process (Fig. 6). At the level of combined histone methylation and acetylation, BCL6 is significantly upregulated in SLE CD4⁺ T cells, recruiting EZH2 and HDAC5 to the miR-142 promoter; this complex increases H3K27me3 while reducing H3K9/K14 acetylation, dually suppressing miR-142-3p/5p expression, thereby inducing CD4⁺ T-cell hyperactivity and driving CD40L/ICOS/IL-21-mediated B-cell hyperstimulation and autoantibody production.404In RA, the histone demethylase JMJD1C extends the functional scope of chromatin-modifying enzymes beyond their canonical histone substrates. B-cell-specific Jmjd1c expression protects mice from collagen-induced arthritis, and in human RA patients, JMJD1C expression in B cells inversely correlates with PC frequency and disease severity.405 Mechanistically, Jmjd1c demethylates Stat3 at Lys140 rather than histone substrates, promoting Ptpn6 (SHP-1)-mediated Stat3 dephosphorylation; in its absence, sustained Stat3 hyperactivation drives excessive PC differentiation.405 This finding expands the functional repertoire of histone-modifying enzymes to nonhistone substrates, with implications for how chromatin-regulatory machinery governs B-cell fate decisions.Beyond substrate expansion, studies in pSS revealed a further complexity: histone modifications and epitranscriptomic RNA modifications operate in concert to drive B-cell dysfunction. In multiple B-cell subsets from the peripheral blood and salivary glands of pSS patients, METTL3 and EZH2 are both significantly upregulated, with expression levels positively correlating with EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) scores.406 RNA immunoprecipitation and actinomycin D chase experiments confirmed that METTL3 directly binds EZH2 mRNA and catalyzes its m6A modification, enhancing EZH2 mRNA stability and sustaining EZH2 overexpression in pSS B cells. The upregulated EZH2, as the catalytic subunit of PRC2, deposits H3K27me3 at the CDKN1A (p21) locus, leading to transcriptional silencing of this cell cycle inhibitor.Building on the histone modification dysregulation described across SLE, RA, and pSS, histone-modifying enzyme inhibitors—particularly HDAC inhibitors, with EZH2 inhibition emerging as a complementary axis—have emerged as tractable therapeutic strategies, predominantly tested in lupus and Sjögren’s models to date. ACY-738, a selective HDAC6 inhibitor, rebalances bone marrow B-cell developmental checkpoints, increases early B-cell subsets while reducing aberrantly expanded mature recirculating B cells, and significantly reduces proteinuria and splenomegaly in lupus-prone female NZB/W F1 mice.407,408 Broader HDAC inhibition also shows therapeutic potential: panobinostat, a pan-HDAC inhibitor, significantly reduces autoreactive PCs in MRL/lpr mice.409 Interestingly, gut microbiota-derived short-chain fatty acids (SCFAs) function as natural HDAC inhibitors with dose-dependent effects—high doses inhibit PC differentiation and B-cell CSR, while low doses moderately enhance these processes.410 At the molecular level, SCFAs (particularly butyrate and propionate) inhibit HDAC activity in B cells, increasing histone acetylation at miRNA host gene loci and upregulating specific miRNAs that target Aicda and Prdm1 mRNA 3’UTRs, thereby suppressing AID and Blimp-1 expression and ultimately reducing CSR, SHM, and PC differentiation.410 However, the therapeutic effects of HDAC inhibitors are subject to hormonal modulation. Estrogen reverses HDAC inhibitor effects on CSR by downregulating miR-26a.411 In contrast, resveratrol-mediated SIRT1 activation upregulates FcγRIIB expression through deacetylation of p65 NF-κB at K310, promoting phospho-p65 (S536) binding to the Fcgr2b promoter and ultimately reducing B-cell numbers and autoantibody production.412 In experimental Sjögren’s syndrome (ESS) mice, pharmacological EZH2 inhibition restored Cdkn1a expression, enhanced B cell apoptosis, and alleviated SS-like symptoms with reduced autoantibody production.406 These findings establish the METTL3–m6A–EZH2–CDKN1A axis as a druggable pathway for pSS therapy, positioning epitranscriptomic RNA modifications as upstream regulators of histone remodeling. Importantly, however, current pan-HDAC and EZH2 inhibitors remain unlikely to displace B-cell-depleting biologics in autoimmune disease unless deployed at narrow, well-defined indications, given their genome-wide pleiotropy and attendant hematopoietic and off-target immune toxicities; meaningful translational progress will therefore depend on identifying biologically specific, B-cell-selective intervention nodes.Chromatin accessibility changesThe convergent changes in DNA methylation and histone modifications ultimately integrate into detectable shifts in chromatin accessibility patterns; in turn, the degree of chromatin openness directly determines transcription factor binding and downstream gene expression. Multi-omics profiling (DNA methylation, ATAC-seq, and RNA-seq) of five circulating B-cell subsets revealed that the SLE epigenetic program is established as early as the resting-naïve (rN) stage, preceding overt activation: SLE rN B cells are already epigenetically primed, carrying a 6,664-locus differential-methylation disease signature and increased chromatin accessibility and expression at genes such as IFI44, STAT4, FOSL2, NR4A1, and NR4A3 (Fig. 6)—with NR4A1 (Nur77) and NR4A3 induced by BCR and TLR signaling, respectively, indicating that naïve SLE B cells have already received antigenic and innate stimulation. Accordingly, CD69 is already overexpressed in SLE rN cells, whereas conventional activation markers (CD86) and effector factors (TBX21/T-bet, ITGAX/CD11c, AICDA) rise only from the activated-naïve (aN) stage onward.31 Chromatin accessibility further resolves pathogenic DN2 B cells, whose regulatory landscape is programmed predominantly by T-bet, AP-1, and EGR family transcription factors and is functionally enriched for BCR/TCR signaling, co-stimulation, and TLR/LPS response programs. Notably, SLE DN2 cells activate an ATF3 response pathway: ATF3, induced by BCR and TLR stimulation and cellular stress, reaches maximal expression and peak motif accessibility in SLE DN2 cells (with ~87% of its predicted target genes upregulated), providing a mechanistic link between BCR/TLR stimulation and the pathogenic DN2 chromatin state.31 In MS, chromatin accessibility studies provide an independent genetic argument for the disease-driving role of B cells: integrating MS GWAS data with ATAC-seq profiles across 16 hematopoietic cell populations, Guo et al. found that MBC open chromatin regions make a statistically significant and independent contribution to MS heritability, refining the driver subsets to MBCs and, among CD4⁺ T cells, Th17 cells.413 Although both MBC and CD4⁺ T (Th17) cells emerged as independent genetic drivers, this B-cell-intrinsic heritability enrichment establishes memory B cells as a key, genetically supported disease-driving population in MS.Epitranscriptomic modificationsBeyond DNA methylation and histone modifications, epitranscriptomic modifications—including A-to-I editing, tRNA m7G, and mRNA m6A modification—have emerged as important regulators of B-cell function and autoimmune pathogenesis, with SLE providing the most comprehensive characterization of RNA epitranscriptomic dysregulation to date. At the level of A-to-I RNA editing, the ADAR1 p150 isoform restrains MDA5-MAVS–driven autoinflammation and is required for B-cell development, and its loss causes severe B-cell deficiency.414 At the level of tRNA modification, the m7G writer METTL1 and its cofactor WDR4 are significantly upregulated in SLE B cells, enhancing m7G modification of specific tRNA species (Fig. 6); this modification selectively amplifies translation of BCR signaling proteins—including CD19, SYK, BTK, and the PI3K–AKT signaling axis—and mitochondrial electron transport chain components, promoting autoreactive B-cell expansion, autoantibody production, and disease progression.415 At the level of mRNA m6A modification, m6A reader and eraser proteins have been functionally characterized in SLE B cells, collectively constituting a multilayered regulatory network. Among m6A readers, Ythdf1 binds m6A sites in the Ighg1 3’UTR, forming nuclear granules that protect the mRNA from degradation and sustain IgG production; Ythdf1 deficiency reduces IgG levels.304 In SLE patients, elevated YTHDF1 expression in ASCs correlates with autoantibody titers and declines following treatment, and inhibitors targeting Ythdf1–m6A interactions reduce autoantibody production in lupus mouse models.304 Among m6A erasers, FTO is highly expressed in ABCs from SLE patients and correlates with renal immune damage; TLR7-MyD88 signaling upregulates FTO, which promotes ABC differentiation through ATP6V1G1 mRNA m6A demethylation;416Fto deficiency, conversely, impairs lysosomal function, blocks ABC differentiation, and ameliorates autoimmunity in lupus-prone mice.416ALKBH5-mediated m6A demethylation of FOXO1 mRNA in monocytic myeloid-derived suppressor cells (M-MDSCs) upregulates FOXO1 expression, which negatively correlates with SLE disease activity;417 loss of FOXO1 in M-MDSCs disrupts the MET/COX-2/PGE2 signaling axis, driving B-cell proliferation and hyperactivation417—revealing that epitranscriptomic modifications can govern B-cell behavior through myeloid intermediaries.ncRNA regulatory networksBeyond the chemical modification mechanisms described above, ncRNAs constitute another core regulatory layer of B-cell dysfunction in autoimmune diseases; miRNAs, lncRNAs, and virus-derived ncRNAs collectively form a multilayered regulatory network influencing B-cell activation, differentiation, and autoantibody production, with convergent targeting pathways emerging across multiple diseases.In SLE, miR-7 and miR-21 cooperatively suppress PTEN and PDCD4, driving B-cell differentiation toward autoreactive ASCs. miR-7 is upregulated in SLE B cells and targets PTEN, thereby relieving its negative regulation of PI3K/AKT; in MRL/lpr mice, miR-7-mediated PTEN downregulation promotes plasmablast/PC differentiation and spontaneous GC formation, accompanied by STAT3 phosphorylation and elevated IL-21;418 antagomiR-7 corrects B-cell abnormalities in a PTEN-dependent manner.418 miR-21 promotes B-cell hyperresponsiveness by downregulating PDCD4, functionally overlapping with miR-7;419 anti-miR-21 treatment reverses splenomegaly in B6.Sle123 mice.419 At the level of B-cell subset-specific regulation, DN2 B cells represent an expanded pathogenic subset in SLE; miR-17-5p directly targets the IL10 3’UTR, and downregulation of miR-17-5p/miR-20a-5p in DN2 B cells leads to IL-10 overexpression; the E2F2–miR-17-5p circuit significantly correlates with disease activity across two independent cohorts.420 In contrast, miR-155 serves as a core regulator of GC reactions; genetic ablation of miR-155 reduces B-cell activation and proliferation in lupus-prone mice by derepressing SHIP-1.421 The regulatory role of miR-155 in GC B cells in SLE is not an isolated phenomenon—this node plays an equally central role in RA. In CD19+ B cells from RA patients, miR-155 is significantly elevated, particularly in the IgD-CD27- B-cell subset from ACPA-positive patients422; this expression pattern is further validated in synovial-derived B cells, where miR-155 levels inversely correlate with transcription factor PU.1 expression, establishing a miR-155–PU.1 axis422; experimental inhibition of miR-155 restores PU.1 expression and significantly reduces antibody production422(Fig. 6), paralleling the SLE mechanism and identifying miR-155 as a shared ncRNA therapeutic target across diseases. The dysregulated miRNA repertoire in RA B cells extends further: small RNA sequencing of CD19⁺ B cells identified 27 differentially expressed miRNAs (e.g., miR-223-3p, miR-486-3p) in methotrexate (MTX)-treated RA, targeting B-cell-activation genes, including STAT3, PRDM1, and PTEN.423 Functionally, miR-29a-deficient mice show defective GC responses with reduced B-cell proliferation and antibody production, conferring near-complete protection from collagen-induced arthritis.424Beyond miRNAs, lncRNA XIST directly links X chromosome dosage to B-cell epigenetic dysregulation in SLE. The striking 9:1 female-to-male incidence ratio425 is supported by chromosomal evidence: 47,XXY (Klinefelter’s syndrome) and 47,XXX (Triple X syndrome) karyotypes confer elevated SLE risk, while 45,X (Turner syndrome) reduces it,426,427 establishing X chromosome dosage as a determinant of susceptibility.428 The XIST ribonucleoprotein (RNP) complex carries multiple autoantigenic components; transgenic Xist expression in male mice is sufficient to induce autoantibodies and exacerbate multi-organ pathology in the pristane-induced lupus model, because the XIST RNP—enriched for nucleic-acid–associated protein autoantigens—serves as an autoantigen source that activates autoreactive lymphocytes;429 autoantibodies against XIST RNP components are correspondingly detected in human autoimmune patients.429 A direct consequence of increased X-chromosome dosage is escape of the X-linked TLR7 gene from X-inactivation: in women and in men with Klinefelter syndrome, substantial fractions of B cells, monocytes, and plasmacytoid dendritic cells express TLR7 biallelically, conferring heightened TLR7 responsiveness and an increased propensity for class switching to IgG.430 Accordingly, perturbing Xist in female mice reactivates inactive-X genes—including TLR7-pathway components—and is sufficient to trigger lupus-like autoimmunity with expansion of age-associated and GC B cells.431 In female SLE patients, XIST dysregulation permits the escape of XIST-dependent genes such as TLR7 from X-inactivation, particularly in ABCs; mechanistically, the B-cell-specific XIST cofactor TRIM28 normally enforces silencing through RING-domain–mediated sumoylation of CDK9 and Pol II promoter-proximal pausing, and its loss reactivates these genes (Fig. 6).329 B cells thereby generate pathogenic autoantibodies through DNA methylation-dependent mechanisms,29 integrating sex chromosome effects with epigenetic regulation.432In contrast to the B-cell-intrinsic ncRNA regulatory patterns in SLE and RA, the ncRNA network in pSS additionally features virus-derived ncRNA transfer across cell types. miR-30b-5p is significantly downregulated in CD19+ B cells from pSS patients across two independent cohorts;433 its inhibition leads to elevated BAFF levels, driving the survival and proliferation of autoreactive B cells through BAFF-mediated signaling.433 Moreover, EBV-infected B cells transfer ebv-miR-BART13-3p to salivary gland epithelial cells via exosomes, where it directly targets the 3’UTR and coding sequence of STIM1 and the AQP5 3’UTR, reducing STIM1 and AQP5 expression and impairing NFAT-dependent transcriptional activity—thereby propagating B-cell epigenetic aberrations to target organs via intercellular communication.434Infectious diseasesIf autoimmune diseases represent the failure of epigenetic safeguards from within, infectious diseases illustrate how exogenous pathogens actively subvert the same B-cell epigenetic machinery to establish persistent infection, evade immune clearance and—in the case of oncogenic herpesviruses—drive malignant transformation. Chief among these is EBV, which infects over 90% of the adult human population and latently persists in MBCs for the host’s lifetime, having evolved a particularly multilayered epigenetic program; bacterial pathogens and systemic inflammatory stimuli exert equally consequential epigenetic pressure on B cells. In parallel, host B-cell epigenomes integrate signals from pathogens and vaccines through dynamically regulated ncRNA circuits, and MBCs encode their accelerated recall capacity in stable chromatin accessibility landscapes.DNA methylationIn EBV-infected Burkitt lymphoma cells, DNMT1 and DNMT3B protein and mRNA levels are markedly elevated during latency I compared with latency III cell lines; however, siRNA-mediated knockdown of either methyltransferase alone fails to derepress EBNA2 or LMP1 or to significantly alter Cp promoter methylation, revealing that elevated DNMT1/DNMT3B are dispensable for maintaining restricted latency.435 In the murine gammaherpesvirus 68 (MHV68) model, Dnmt3a/Dnmt3b-deposited CpG methylation at the distal gene 50 promoter suppresses viral reactivation; conditional B-cell deletion of these enzymes elevates lytic gene 50 expression in vivo, although methylation eventually rebounds via DNMT3-independent mechanisms.436 Conversely, methionine restriction depletes S-adenosylmethionine (SAM) availability and disrupts the interconnected methionine–folate cycles that sustain DNMT-dependent silencing of EBV genomes, driving global demethylation at latent and lytic promoters and triggering transcriptional reactivation of LMP1, BZLF1, and BMRF1—an effect recapitulated by CRISPR disruption of methionine cycle enzymes.437Histone modificationsEBNA2 drives histone acetylation of the host genome through liquid–liquid phase separation: its N-terminal domain nucleates accessible chromatin domains (ACDs), while the C-terminal domain recruits the acetyltransferase p300 to these ACDs, depositing activating acetylation marks and reorganizing chromatin topology to sustain viral latency gene expression.438 At the genome scale, EBV oncoproteins and NF-κB subunits co-occupy 187 super-enhancer loci defined by exceptionally broad H3K27ac signals, driving epigenetic activation of MYC and BCL2 to sustain lymphoblast proliferation and survival.439 The HDAC inhibitor zabadinostat dose-dependently induces H3 hyperacetylation and upregulates CIITA, driving robust MHC I/II gene expression and promoting dendritic cell maturation as well as T- and B-cell activation; in vaccine settings, zabadinostat co-administration further amplifies antigen-specific CD8+ effector memory T cells and broad Th1/Th2/Th17 cytokine responses, suggesting that HDAC inhibition-mediated histone hyperacetylation improves COVID-19 vaccine immunogenicity by enhancing antigen presentation and immune cell activation.440EBV latent infection is enforced by a dual histone-methylation strategy in which EBNA3 proteins recruit PRC2-mediated H3K27me3 to both host differentiation and viral reactivation loci, while SUV39H1 deposits H3K9me3 specifically at the BZLF1 promoter. Mechanistically, EBNA3A and EBNA3C bind near the transcription start sites of CDKN2C (p18INK4c) and PRDM1, recruiting EZH2 to elevate H3K27me3 levels and stably repress PC differentiation programs.441 Concurrently, EBNA3A antagonizes EBNA2 at CBF1/RBPJ–EBNA2-occupied intergenic enhancers between CXCL10 and CXCL9, reducing H3K27ac and RNA polymerase II occupancy before progressive H3K27me3 spreading across the domain.442 At the viral BZLF1 promoter, SUV39H1-deposited H3K9me3 enforces transcriptional silencing in B95-8 cells: SUV39H1 overexpression dose-dependently suppresses BZLF1 promoter activity, whereas its SET-domain deletion or chaetocin-mediated inhibition derepresses BZLF1, and chaetocin synergizes with HDAC inhibitors (SAHA or butyrate) to elevate BZLF1 transcription up to 18.9-fold.443 Complementarily, the nucleic acid-binding protein SFPQ reinforces BZLF1 repression by sustaining linker histone H1 expression, whose occupancy at the BZLF1 promoter decreases upon lytic reactivation.444 In addition to PRC2, PRC1 adds a further repressive layer: its subunits RING1 and SCML2 deposit H2AK119Ub1 at the EBV LMP promoters, while UHRF1—reading H3K9me3 and hemimethylated DNA—cooperates with DNMT1 to sustain CpG methylation across the Cp, Wp and LMP promoters. Depletion of these components demethylates and derepresses LMP1, LMP2A and EBNA2 together with the lytic-switch gene BZLF1, demonstrating that DNA methylation and PRC1-mediated histone ubiquitylation nonredundantly enforce EBV latency.445Chromatin remodeling and accessibility changesEBV reprograms chromatin accessibility through viral–host remodeling complex interplay to drive B-cell transformation. High-resolution scATAC-seq reveals that EBV infection bifurcates B cells into stalled (EBV+-low ATAC) and immortalized (EBV+-high ATAC) trajectories, whereby EBNA2/3C/LP-bound sites undergo chromatin closure at key B-cell activation and cytokine signaling genes (IL21R, CD58, and MAPK8), whereas immortalization is characterized by enhanced accessibility at latent-phase regulatory elements such as NFKBIA and RBPJ.446 LMP2A reshapes enhancer landscapes in GC B cells by augmenting H3K4me1 and H3K27ac at loci such as Zbtb20 and Trim12a and globally downregulating NF-κB and BCR signaling enhancers, thereby subverting affinity-based selection, skewing differentiation toward extrafollicular IgM+ plasmablasts, and precipitating lupus-like nephritis with autoreactive antibody production.447 This virus-driven chromatin dysregulation contrasts sharply with the physiological epigenetic programming of antiviral memory B cells, in which T-bet establishes basal accessibility at antiviral gene promoters to enable accelerated recall responses.297ncRNA regulationIn Citrobacter rodentium infection, miR-155 ablation in B cells dampens BCR signaling, reduces Cd19 and Bcl6 expression, impairs GC formation, attenuates antigen-specific IgG and IgA production, and prolongs bacterial persistence, implicating miR-155 as a pivotal amplifier of humoral defense.448 In primary murine splenic B cells stimulated in vitro with Porphyromonas gingivalis LPS, miR-146a reduced IL-1β, IL-6 and IL-10 expression by targeting IRAK1 but not TRAF6.449 In influenza vaccination, dynamic lncRNA expression reprograms GC reactions: MIAT and MCM3AP-AS1 are rapidly downregulated by day 1, LINC01133 emerges by day 3, and DANCR peaks by day 7 alongside upregulation of the B-cell survival gene TNFRSF17; furthermore, the IgH-embedded lncRNA FAM30A correlates with antibody titers, suggesting cis-acting regulation of CSR.331Conclusion and perspectivesIn this review, we traced the epigenetic landscape of humoral immunity from B-cell lineage commitment through GC dynamics to the generation of LLPCs and MBCs. Across these stages, DNA methylation, histone modifications, chromatin remodeling and accessibility changes, RNA epitranscriptomic marks, and ncRNAs function as an integrated, multilayered control system that orchestrates V(D)J recombination, CSR, SHM, and B-cell fate decisions. TET-mediated DNA demethylation cooperates with EBF1-driven chromatin opening to establish B-cell identity;233,293,295 EZH2 deposits H3K27me3 at bivalent promoters to poise GC B cells for rapid fate transitions;262,263 and m6A modifications on Ighg1 mRNA calibrate antibody homeostasis in ASCs.304 Importantly, these layers are deeply interconnected: histone marks recruit chromatin remodelers, DNA methylation patterns constrain transcription factor access, and RNA modifications intersect with histone modifications—as illustrated by the METTL3–EZH2 axis in pSS406—to drive or derail B-cell differentiation programs.A striking illustration of this contextual complexity is provided by EZH2, whose role in PC differentiation is context-dependent and varies with developmental stage, mutational status, and target loci. Genetic EZH2 deficiency impairs plasmablast formation by destabilizing XBP1.264 Pharmacological EZH2 inhibition in division-coupled GC B cells enhances PC commitment by releasing Blimp-1 from a poised H3K27me3 state.298 In SLE B cells, sustained EZH2 overexpression represses BACH2 and drives pathologic PC differentiation.402 In follicular lymphoma, the Y641 gain-of-function mutant traps GC B cells in a self-renewing state.343 These outcomes are not mutually exclusive but reflect EZH2 acting on different target programs in different cellular contexts—a principle that likely extends to many other epigenetic regulators of B-cell biology.When these epigenetic programs go awry, the consequences span a broad disease spectrum. In B-cell malignancies, recurrent mutations in CREBBP, EP300, KMT2D, ARID1A, EZH2, and TET2 reshape enhancer landscapes and super-enhancer architecture to sustain lymphomagenesis.236,247,248,255,256,280,336,343,344,363,364 In metabolic and cardiovascular diseases, chronic metabolic stress elicits B-cell-specific DNA methylation changes376,378 and miRNA-driven cytokine dysregulation—for instance, miR-19a suppresses the anti-inflammatory cytokine IL-10 in B cells from patients with atherosclerosis.379 In autoimmune disorders, studies of SLE, RA, pSS, and MS have identified disease- and cell-type-specific alterations in DNA methylation, histone modifications, and ncRNA networks.390,398,405,406,422,433 Dysregulation of XIST-dependent XCI may contribute to the escape of selected X-linked immune genes and to female-biased autoimmunity.329,429,432 In infectious diseases, EBV commandeers the host epigenetic machinery through EBNA2-driven histone acetylation,438,439 EBNA3-mediated PRC2 recruitment,441,442 and chromatin accessibility reprogramming446 to establish latency and drive oncogenic transformation.Despite these advances, significant gaps and challenges temper the translational outlook. First, the temporal hierarchy among epigenetic modifications during B-cell responses remains poorly defined: it is still unclear which marks are drivers versus consequences of transcriptional change, and how DNA methylation, histone modifications, chromatin accessibility, and RNA modifications are ordered and coordinated as B cells traverse the GC and commit to PC or MBC fates. Second, the functional roles of emerging RNA marks—including ac4C, m7G, and pseudouridine—in B cells remain largely uncharacterized, and most available epigenomic datasets are correlative, lacking the perturbational evidence needed to establish causality. Third, cellular and interindividual epigenetic heterogeneity, increasingly apparent at single-cell resolution, complicates the distinction between disease-specific and generic regulatory programs. Fourth, therapeutic translation is constrained by the genome-wide pleiotropy of current pan-HDAC, DNMT, and EZH2 inhibitors and their attendant hematopoietic and off-target immune toxicities, making it unlikely that these agents will displace B-cell-depleting biologics in autoimmune disease unless restricted to narrow, well-defined indications. Fifth, mechanistic inference is further complicated by species-specific differences between murine and human B-cell epigenomes and by the divergence of in vitro transformed cell lines from genuine in vivo GC biology. Finally, epigenetic insight is unevenly distributed across disease contexts: whereas B-cell malignancies and classical autoimmune diseases are supported by mechanistically deep, high-resolution studies, the B-cell-intrinsic epigenetics of metabolic and cardiovascular disease rests largely on small, correlative studies with limited mechanistic or causal depth, and its intersection with neurodegenerative disease pathogenesis remains almost entirely unexplored, with existing work either characterizing B-cell phenotypes without epigenetic depth or interrogating non-B-cell populations within the central nervous system.Addressing these gaps will require the convergence of new technologies with more precise interventions. Single-cell multi-omic and spatial epigenomic approaches are well positioned to resolve the temporal and spatial ordering of epigenetic marks across GC dark and light zones and extrafollicular niches, while humanized and organoid models may narrow the gap between murine mechanisms and human disease. At the most precise scale, locus-specific epigenetic editing—catalytically inactive Cas9 (dCas9) fused to DNMT3A, TET1, or p300—now permits causal interrogation of the individual regulatory elements highlighted in this review,450,451 thereby moving the field from correlation toward mechanism. Therapeutically, the validated druggability of DNMT, HDAC, and EZH2 in B-cell malignancies is being refined toward biologically specific, B-cell-selective nodes—such as the JMJD1C/STAT3 axis in RA405 and the FTO/TLR7 axis in SLE.416 Such interventions are increasingly paired with nanoparticle-based delivery, exemplified by lipid-nanoparticle (LNP)–encapsulated anti-miR-130b oligonucleotides that showed antitumor activity with minimal toxicity in a murine A20 B-cell lymphoma model.371 Epigenetic agents may also serve as vaccine adjuvants or partners with immune checkpoint blockade, leveraging histone hyperacetylation to enhance antigen presentation. In parallel, methylation-based biomarkers—including the CLL maturation subtypes (LP/IP/HP-CLL)30 and SLE transitional B-cell CpG signatures390—warrant prospective clinical validation as diagnostic and prognostic tools. 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Shaocun Zhang is supported by a Postdoctoral Fellowship Program (Grade B) of the China Postdoctoral Science Foundation (GZB20250557) and the Young Scientists Fund of the National Natural Science Foundation of China (Grant No. 82502174). Yu Wang is supported by a fellowship from the China Postdoctoral Science Foundation (2025M781380). This study is also supported by research funds from the Center for Life Sciences and the Institute for Immunology at Tsinghua University.Author informationAuthor notesThese authors contributed equally: Shaocun Zhang, Yu WangAuthors and AffiliationsDepartment of Rheumatology and Immunology, Peking University Third Hospital, Beijing, ChinaShaocun ZhangState Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Key Laboratory for Sleep Breathing Disorder, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, ChinaShaocun Zhang, Yu Wang, Xin Min & Wanli LiuInstitute of Immunology, PLA, Third Military Medical University (Army Medical University), Chongqing International Institute for Immunology, Chongqing, ChinaYuzhang WuAuthorsShaocun ZhangView author publicationsSearch author on:PubMed Google ScholarYu WangView author publicationsSearch author on:PubMed Google ScholarXin MinView author publicationsSearch author on:PubMed Google ScholarYuzhang WuView author publicationsSearch author on:PubMed Google ScholarWanli LiuView author publicationsSearch author on:PubMed Google ScholarContributionsWanli Liu, Shaocun Zhang, Yuzhang Wu, and Yu Wang conceived the topic and central idea. Shaocun Zhang, Yuzhang Wu, Yu Wang, and Xin Min conducted the literature search. Shaocun Zhang, Yu Wang, and Xin Min wrote the original manuscript and prepared the figures. Wanli Liu, Shaocun Zhang, Yu Wang, Yuzhang Wu, and Xin Min revised the manuscript. All the authors have read and approved the final manuscript.Corresponding authorsCorrespondence to Yuzhang Wu or Wanli Liu.Ethics declarationsCompeting interestsThe authors declare no competing interests.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Rights and permissionsOpen Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. 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