Data availabilityPublicly available RNA-seq datasets were used for transcriptomic comparisons: Tbx5 cKO: GEO databases GSE129503 and GSE239805; AngII: National Center for Biotechnology Information (NCBI) under BioProject ID PRJNA470522; Zfhx3 KO: GEO database GSE229525; and Scn1b-null: GEO database GSE152617. Publicly available CAGE-seq (GSE150736) and ChIP−seq (GSE215065) datasets were used. For the remaining datasets, raw and processed sequencing data generated in this study have been deposited in the NCBI’s GEO and are accessible through GEO Series accession number GSE311509. Source data for main figures are provided in File 1. Source data for extended data and supplementary figures are provided in File 2.Code availabilityCustom code was not developed to perform the work in this study. Data analyses were performed using base R libraries, CRAN libraries and Bioconductor libraries cited in the Methods section. 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This work was supported by the National Institutes of Health (NIH), including R01 HL148719 (I.P.M. and A.J.R.) and R01 HL163523 (I.P.M. and S.P.), F30HL131298 (R.D.N.), T32HL007381 (S.L. and R.D.N.) and T32HD055164 (S.L.). T.A.M. was supported by NIH grants R01HL171711 and HL181226 and an American Heart Association (AHA) Collaborative Sciences Award (24CSA1255857). D.J.C. was supported by F32HL160099, T.M.V. and T.A.M. by HL150225, T.M.V. by HL105699 and M.R.G. by AHA CDA34660084. A.J.R. was supported by R35 GM145373. N.Y. was supported by T32HL098129. D.S.P. was supported by R01 HL165130 and R01 HL171989.Author informationAuthors and AffiliationsDepartment of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL, USASonja Lazarevic, Carlos Perez-Cervantes, Zhezhen Wang, Kaitlyn M. Shen, Margaret Gadek, Yildiz Koca, Rangarajan D. Nadadur & Ivan P. MoskowitzLeon H. Charney Division of Cardiology, New York University Langone Health, New York, NY, USAJunhua Xiao, Naoko Yamaguchi & David S. ParkDepartment of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL, USAJohnathon M. Hall & Alexander J. RuthenburgDepartments of Anesthesiology & Perioperative Medicine, Medicine and Physiology, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USADouglas J. Chapski & Thomas M. VondriskaDepartment of Cellular and Molecular Signaling, The Institute of Biomedicine and Biotechnology of Cantabria, CSIC-University of Cantabria, Santander, SpainManuel Rosa-GarridoDepartment of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO, USAMarcello Rubino & Timothy A. McKinseyDepartment of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USASebastian PottAuthorsSonja LazarevicView author publicationsSearch author on:PubMed Google ScholarCarlos Perez-CervantesView author publicationsSearch author on:PubMed Google ScholarZhezhen WangView author publicationsSearch author on:PubMed Google ScholarKaitlyn M. ShenView author publicationsSearch author on:PubMed Google ScholarMargaret GadekView author publicationsSearch author on:PubMed Google ScholarJunhua XiaoView author publicationsSearch author on:PubMed Google ScholarNaoko YamaguchiView author publicationsSearch author on:PubMed Google ScholarJohnathon M. HallView author publicationsSearch author on:PubMed Google ScholarYildiz KocaView author publicationsSearch author on:PubMed Google ScholarDouglas J. ChapskiView author publicationsSearch author on:PubMed Google ScholarManuel Rosa-GarridoView author publicationsSearch author on:PubMed Google ScholarMarcello RubinoView author publicationsSearch author on:PubMed Google ScholarRangarajan D. NadadurView author publicationsSearch author on:PubMed Google ScholarTimothy A. McKinseyView author publicationsSearch author on:PubMed Google ScholarThomas M. VondriskaView author publicationsSearch author on:PubMed Google ScholarAlexander J. RuthenburgView author publicationsSearch author on:PubMed Google ScholarSebastian PottView author publicationsSearch author on:PubMed Google ScholarDavid S. ParkView author publicationsSearch author on:PubMed Google ScholarIvan P. MoskowitzView author publicationsSearch author on:PubMed Google ScholarContributionsS.L. and I.M. conceptualized the study, interpreted the data and wrote the manuscript. C.P.C., Z.W. and Y.K. performed the data analysis for the manuscript. S.L., D.P. and I.M. conceived and designed the TAC experiments. D.P., N.Y. and J.X. performed the surgery and analyzed the relevant data. S.L. generated the libraries for sequencing. S.L., K.M.S., M.G., R.D.N. and I.M. conceived, designed and performed the ATAC−seq datasets and the Tbx5 cKO RNA-seq and ncRNA-seq experiments. C.P.P. and Z.W. analyzed the datasets. D.J.C., M.R.G., M.R., T.A.M. and T.M.V. conceived, performed and analyzed the Hi-C experiment in fibroblasts. C.P.P. additionally analyzed the data. S.L., I.M. and S.P. conceived and designed the snRNA-seq dataset; S.P. performed the experiment; and C.P.P. and Y.K. analyzed the dataset. J.M.H. and A.J.R. conceived, designed and performed the Micro-C experiment, and C.P.P. analyzed the dataset.Corresponding authorCorrespondence to Ivan P. Moskowitz.Ethics declarationsCompeting interestsT.A.M. is a co-founder of Myracle Therapeutics, is on the scientific advisory boards of Eikonizo Therapeutics and Revier Therapeutics and is a consultant for Augustine Therapeutics. D.S.P. is an educational consultant for Biotronik and receives research support from Xentria. The remaining authors declare no competing interests.Peer reviewPeer review informationNature Cardiovascular Research thanks Svetlana Reilly and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 Comparison of gene expression in left atrial samples between Tbx5 cKO mice and TAC mice.a, Venn diagram comparing the downregulated (a, left) and upregulated (a, right) differentially expressed genes in the Tbx5 cKO and TAC mouse models. Differential expression analysis was performed using DESeq2. P-values were calculated using the Wald test (two-sided) with Benjamini-Hochberg correction for multiple comparisons. b,c, GO terms for the downregulated (b) genes and upregulated genes (c) in the Tbx5 cKO and TAC mouse models. Gene Ontology enrichment analysis was performed using Metascape. Statistical significance was determined using the hypergeometric test with Benjamini-Hochberg correction for multiple comparisons. Dot size represents gene ratio; color intensity represents -log10(p-value). d-e, Violin plot [CPM] (d) and scatterplot [TPM] (e) for the control mice (R26CreERT2) in the Tbx5 cKO RNA-seq and control mice (sham) in the TAC RNA-seq. Statistical significance in the violin plot was determined using a two-sided t-test. Data points in the scatterplot represent average TPM for individual genes, and the grey line represents the best fit across all genes. P-values were calculated using Pearson correlation. Exact p-values are reported where computationally feasible; p