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Here we show changes to alpha and beta cell-specific methylomes and transcriptomes from people with or without T2D, using whole-genome bisulfite sequencing and RNA sequencing. We discover 22,544 differentially methylated regions annotated to 7,975 genes in alpha versus beta cells, such as\n                    <jats:italic>INS<\/jats:italic>\n                    ,\n                    <jats:italic>GCG<\/jats:italic>\n                    ,\n                    <jats:italic>PDX1<\/jats:italic>\n                    and\n                    <jats:italic>PCSK1<\/jats:italic>\n                    , with ~50% showing differential expression. CRISPR\u2013dCas9\u2013DNMT3A-based epigenetic editing increases\n                    <jats:italic>INS<\/jats:italic>\n                    and\n                    <jats:italic>TH<\/jats:italic>\n                    DNA methylation, while CRISPR\u2013dCas9\u2013TET1-based editing decreases\n                    <jats:italic>GCG<\/jats:italic>\n                    methylation, each altering\n                    <jats:italic>INS, TH<\/jats:italic>\n                    or GCG expression and content in beta cells. Pre-T2D\/T2D-associated differentially methylated regions in alpha and beta cells overlap 12\u201318% of T2D-associated genome-wide association study candidates. Additionally,\n                    <jats:italic>ONECUT2<\/jats:italic>\n                    is epigenetically upregulated in beta cells from people with pre-T2D\/T2D and elevated in male Goto-Kakizaki rat islets. ONECUT2 overexpression in beta cells\/islets downregulates gene sets impacting insulin secretion and glucose homeostasis, and reduces mitochondrial activity, ATP\/ADP ratio and insulin secretion. We also provide \u2018alpha-beta-methylome\u2019 (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/alpha-beta-methylome.serve.scilifelab.se\/app\/alpha-beta-methylome\/\" ext-link-type=\"uri\">https:\/\/alpha-beta-methylome.serve.scilifelab.se\/app\/alpha-beta-methylome\/<\/jats:ext-link>\n                    ), a resource exploring T2D, age and sex associations on methylation, highlighting cell-specific epigenetic regulation and dysfunctions contributing to T2D.\n                  <\/jats:p>","DOI":"10.1038\/s42255-026-01498-9","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T09:02:55Z","timestamp":1777021375000},"page":"957-980","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6484-1544","authenticated-orcid":false,"given":"Jones K.","family":"Ofori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Ruhrmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1641-0406","authenticated-orcid":false,"given":"Axel","family":"Lindstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Perfilyev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melina","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8458-1065","authenticated-orcid":false,"given":"Alexandros","family":"Karagiannopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3636-4298","authenticated-orcid":false,"given":"Lucia","family":"Scisciola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Kost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0709-2828","authenticated-orcid":false,"given":"Josefine","family":"J\u00f6nsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c5sa","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Kantor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Dudenh\u00f6ffer-Pfeifer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne G.","family":"Rots","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Wendt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"R\u00f6nn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6467-5029","authenticated-orcid":false,"given":"Lena","family":"Eliasson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2461-9073","authenticated-orcid":false,"given":"Karl","family":"Bacos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0587-7154","authenticated-orcid":false,"given":"Charlotte","family":"Ling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,24]]},"reference":[{"key":"1498_CR1","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1210\/er.2018-00251","volume":"40","author":"NJ Wewer Albrechtsen","year":"2019","unstructured":"Wewer Albrechtsen, N. 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