CommentPublished: 29 July 2026Sarah Hoelzl ORCID: orcid.org/0000-0003-0308-85221,2 &Daniel Andergassen ORCID: orcid.org/0000-0003-1196-42891,2 Nature Reviews Molecular Cell Biology (2026) Cite this articleSave articleView saved researchSubjectsGene silencingRNA metabolismSex-biased diseases may arise from differential expression of genes escaping X-chromosome inactivation in female individuals; however, causality remains mostly unproven. To help find escape genes that cause sex-biased disease, we present an in vivo workflow to pinpoint when and where escape matters, prioritize conserved candidate genes, and experimentally manipulate their expression.This is a preview of subscription content, access via your institutionAccess optionsAccess Nature and 54 other Nature Portfolio journalsGet Nature+, our best-value online-access subscription27,99 € / 30 dayscancel any timeLearn moreSubscribe to this journalReceive 12 print issues and online access269,00 € per yearonly 22,42 € per issueLearn moreBuy this articlePurchase on SpringerLinkInstant access to the full article PDF.39,95 €Prices may be subject to local taxes which are calculated during checkoutReferencesLoda, A., Collombet, S. & Heard, E. Gene regulation in time and space during X-chromosome inactivation. Nat. Rev. Mol. Cell Biol. 23, 231–249 (2022).Article PubMed Google Scholar Liu, A. et al. Genetic drivers and cellular selection of female mosaic X chromosome loss. Nature 631, 134–141 (2024).Article PubMed PubMed Central Google Scholar Sano, S. et al. Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality. Science 377, 292–297 (2022).Article PubMed PubMed Central Google Scholar Berletch, J. B. et al. Escape from X inactivation varies in mouse tissues. PLoS Genet 11, e1005079 (2015).Article PubMed PubMed Central Google Scholar Gadek, M. et al. Aging activates escape of the silent X chromosome in the female mouse hippocampus. Sci. Adv. 11, eads8169 (2025).Article PubMed PubMed Central Google Scholar Hoelzl, S., Hasenbein, T. P., Engelhardt, S. & Andergassen, D. Aging promotes reactivation of the Barr body at distal chromosome regions. Nat. Aging 5, 984–996 (2025).Article PubMed PubMed Central Google Scholar Souyris, M. et al. TLR7 escapes X chromosome inactivation in immune cells. Sci. Immunol. 3, eaap8855 (2018).Article PubMed Google Scholar Hasenbein, T. P., Hoelzl, S., Engelhardt, S. & Andergassen, D. Allele-specific genomics decodes gene targets and mechanisms of the non-coding genome. Nucleic Acids Res. 53, gkaf912 (2025).Article PubMed PubMed Central Google Scholar Tomofuji, Y. et al. Quantification of escape from X chromosome inactivation with single-cell omics data reveals heterogeneity across cell types and tissues. Cell. Genom. 4, 100625 (2024).Article PubMed PubMed Central Google Scholar DeCasien, A. R. et al. Sex effects on gene expression across the human cerebral cortex at cell type resolution. Science 392, eaea9063 (2026).Article PubMed Google Scholar Gylemo, B., Bensberg, M. & Nestor, C. E. A whole-organism landscape of X-inactivation in humans. eLife 14, RP102701 (2025).Article PubMed PubMed Central Google Scholar Tukiainen, T. et al. Landscape of X chromosome inactivation across human tissues. Nature 550, 244–248 (2017).Article PubMed PubMed Central Google Scholar Oliva, M. et al. The impact of sex on gene expression across human tissues. Science 369, eaba3066 (2020).Article PubMed PubMed Central Google Scholar Rodriguez-Montes, L. et al. Sex-biased gene expression across mammalian organ development and evolution. Science 382, eadf1046 (2023).Article PubMed PubMed Central Google Scholar Gemberling, M. P. et al. Transgenic mice for in vivo epigenome editing with CRISPR-based systems. Nat. Methods 18, 965–974 (2021).Article PubMed PubMed Central Google Scholar Download referencesAuthor informationAuthors and AffiliationsInstitute of Pharmacology and Toxicology, Technical University Munich, Munich, GermanySarah Hoelzl & Daniel AndergassenDZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, GermanySarah Hoelzl & Daniel AndergassenAuthorsSarah HoelzlView author publicationsSearch author on:PubMed Google ScholarDaniel AndergassenView author publicationsSearch author on:PubMed Google ScholarCorresponding authorCorrespondence to Daniel Andergassen.Ethics declarationsCompeting interestsThe authors declare no competing interests.Peer reviewPeer review informationNature Reviews Molecular Cell Biology thanks the anonymous reviewer(s) for their contribution to the peer review of this work.Rights and permissionsReprints and permissionsAbout this article