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A naturally occurring mutation in the gene encoding the essential islet-enriched transcription factor MafA (\n                      <jats:italic>MafA<\/jats:italic>\n                      <jats:sup>S64F<\/jats:sup>\n                      ) produces an unusually long-lived variant protein that predisposes male carriers to MODY. Here we investigated how genetic background modulates disease penetrance in\n                      <jats:italic>Mafa<\/jats:italic>\n                      <jats:sup>S64F\/+<\/jats:sup>\n                      male mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Mafa<\/jats:italic>\n                      <jats:sup>S64F\/+<\/jats:sup>\n                      male mice, either on a mixed genetic background (C57BL\/6J and SJL\/J) or backcrossed to a C57BL\/6J background, were assessed for glucose levels, beta cell function and gene signatures associated with cellular ageing. RNA-seq analysis was performed to identify unique differentially expressed genes (DEGS) and pathways in mixed-background or C57BL\/6J\n                      <jats:italic>Mafa<\/jats:italic>\n                      <jats:sup>S64F\/+<\/jats:sup>\n                      male mouse islets. These were overlaid on MafA CUT&amp;RUN peaks to identify direct targets that could differentially impact beta cell function in each background.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Mafa<\/jats:italic>\n                      <jats:sup>S64F\/+<\/jats:sup>\n                      male mice on a mixed background manifested overt diabetes, impaired insulin secretion, accelerated beta cell senescence and dysregulated circadian gene expression, while backcross to C57BL\/6J prevented dysglycaemia and maintained insulin secretion in\n                      <jats:italic>Mafa<\/jats:italic>\n                      <jats:sup>S64F\/+<\/jats:sup>\n                      male mice, comparable with control littermates. RNA-seq of C57BL\/6J\n                      <jats:italic>Mafa<\/jats:italic>\n                      <jats:sup>S64F\/+<\/jats:sup>\n                      male mouse islets revealed relative normalisation of DEGs associated with cellular ageing and circadian regulation. In addition, islets from C57BL\/6J\n                      <jats:italic>Mafa<\/jats:italic>\n                      <jats:sup>S64F\/+<\/jats:sup>\n                      male mice showed unique downregulation of retinoic acid signalling and cell cycle inhibitor p21, the latter of which modulates cellular ageing and diabetes seen in the mixed-background mouse islets. CUT&amp;RUN mapping revealed that MafA directly impacted expression of (at least) retinoic acid receptor-\u03b1 (encoded by\n                      <jats:italic>Rara<\/jats:italic>\n                      ) in islets from C57BL\/6J\n                      <jats:italic>Mafa<\/jats:italic>\n                      <jats:sup>S64F\/+<\/jats:sup>\n                      male mice and circadian regulation in islets from mixed-background mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      In sum, these data show that genetic modifiers can impact beta cell regulation of retinoic acid signalling and circadian entrainment to modulate beta cell ageing and disease penetrance in mice modelling\n                      <jats:italic>MAFA<\/jats:italic>\n                      -MODY.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data availability<\/jats:title>\n                    <jats:p>Sequencing data were deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (accession no. GSE299343 for bulk RNA-seq and GSE298664 for CUT&amp;RUN analyses).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06903-2","type":"journal-article","created":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T17:12:48Z","timestamp":1791738768000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic background modulates MafAS64F-mediated islet ageing in male mice"],"prefix":"10.1007","author":[{"given":"Zachary","family":"Loyd","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongsoo","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mallory","family":"Maurer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizabeth","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Hua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garrett","family":"Reynolds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark P.","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Philippe","family":"Cartailler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Magnuson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeeyeon","family":"Cha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,11]]},"reference":[{"issue":"9","key":"6903_CR1","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.tem.2011.05.003","volume":"22","author":"Y Hang","year":"2011","unstructured":"Hang Y, Stein R (2011) MafA and MafB activity in pancreatic \u03b2 cells. 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Esposito (Kayothera) for advice on retinoic acid signalling experiments, and former and current members of the Cha lab for feedback on this manuscript.","order":1,"name":"Ethics","label":"Acknowledgements","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The datasets generated during and\/or analysed during the current study are available from the corresponding author upon reasonable request after publication of the article. Sequencing data were deposited and are now available in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (accession no. GSE299343 for bulk RNA-seq and GSE298664 for CUT&RUN analyses).","order":2,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"This research was performed using resources and\/or funding provided in parts by NIH grants to JC (K08 DK132507), LJ (T32 DK007563), RS (R01 DK090570), A. Attie from the University of Wisconsin-Madison and MPK (R01DK101573,\u00a0R01DK102948 and RC2DK125961, and the Vanderbilt Diabetes Research and Training Center (DK20593). JC was also supported by a Burroughs Wellcome Fund Career Award for Medical Scientists and generous start-up funding from Vanderbilt University Medical Center. MPK is also supported by the University of Wisconsin-Madison Department of Biochemistry and Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation. Flow cytometry experiments were performed in the Vanderbilt Flow Cytometry Shared Resource, which is supported by the Vanderbilt Ingram Cancer Center (P30 CA068485) and the Vanderbilt Digestive Disease Research Center (DK058404).","order":3,"name":"Ethics","label":"Funding","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","label":"Authors\u2019 relationships and activities","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The study was conceived by JC and designed by ZL, DL, MAM, RS and JC. Funding was obtained by JC and RS. All authors contributed to the acquisition, analysis or interpretation of the data. Data and statistical analyses were performed by ZL, DL, MM, LJ, J-HL, GR, MPK, J-PC and JC. ZL, DL, MPK, JPC, RS and JC drafted the manuscript, and all authors critically revised it for important intellectual content. JC supervised the work. All authors approved the final version of the manuscript. JC takes responsibility for the integrity of the work as a whole.","order":5,"name":"Ethics","label":"Contribution statement","group":{"name":"EthicsHeading","label":"Ethics"}}]}}