CHD3 and CHD4 coordinate gene expression programs to maintain β-cell function and identity in vivo

CHD3 and CHD4 coordinate gene expression programs to maintain β-cell function and identity in vivo | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article CHD3 and CHD4 coordinate gene expression programs to maintain β-cell function and identity in vivo Jason Spaeth, Sukrati Kanojia, Avinil Das Sharma, Rajani George, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7880472/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Pancreatic β cells require tightly regulated chromatin architecture to preserve their identity and sustain glucose-stimulated insulin secretion. Here, we define cooperative and compensatory roles for the NuRD complex remodelers CHD3 and CHD4 in maintaining β-cell function. While β-cell-specific loss of CHD3 alone had little effect, combined deletion of CHD3 and CHD4 caused severe glucose intolerance, impaired insulin secretion, and reduced β-cell area. Transcriptomic and chromatin accessibility analyses revealed downregulation of key β-cell maturity genes, reduced accessibility at β-cell enhancers, and derepression of disallowed, developmental, and alternative islet cell programs, accompanied by altered ion channel expression and defective electrophysiological properties. Mechanistically, CHD3 protein abundance increased upon CHD4 loss and CHD3:PDX1 interactions were dynamically enhanced during early high-fat diet challenge, buffering against β-cell stress before collapsing under chronic conditions. Human pseudoislets recapitulated conserved features of CHD3/4 deficiency, linking these remodelers to human β-cell function. Together, our findings establish CHD3 and CHD4 as cooperative guardians of β-cell transcriptional programs and uncover a compensatory mechanism that transiently preserves β-cell resilience under metabolic stress but fails in diabetes progression. Biological sciences/Molecular biology/Transcriptomics Biological sciences/Molecular biology/Chromatin/Chromatin remodelling Biological sciences/Physiology/Metabolism/Metabolic diseases/Diabetes/Type 2 diabetes Coregulator CHD3 CHD4 Sequencing Insulin Secretion Beta Cell Type 2 Diabetes Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTable1mRNASeq09102025.xlsx Supplementary Table 1 SupplementaryTable2ATACSeq09172025.xlsx Supplementary Table 2 SupplementaryTable3mRNASeqhumanpseudoisletanalysesshCHD34.xlsx Supplementary Table 3 SupplementaryTable4Humanisletdonorinformation.xlsx Supplementary Table 4 SupplementaryFiles.pdf Supplementary Figures Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7880472","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":533548487,"identity":"a160b03e-76c5-410d-88cb-5db17274f588","order_by":0,"name":"Jason 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