Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes.
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Ofori JK, Ruhrmann S, Lindström A, Perfilyev A, Martin M, Karagiannopoulos A, Scisciola L, Kost K, Jönsson J, Nilsson Å, Kantor B, Dudenhöffer-Pfeifer M, Rots MG, Wendt A, Rönn T, Eliasson L, Bacos K, Ling C
Nat Metab 8 (4) 957-980 [2026-04-00; online 2026-04-24]
Epigenome-wide studies of pancreatic islets provide valuable insights into type 2 diabetes (T2D) but lack methylomes from individual cell types. 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 INS, GCG, PDX1 and PCSK1, with ~50% showing differential expression. CRISPR-dCas9-DNMT3A-based epigenetic editing increases INS and TH DNA methylation, while CRISPR-dCas9-TET1-based editing decreases GCG methylation, each altering INS, TH or GCG expression and content in beta cells. Pre-T2D/T2D-associated differentially methylated regions in alpha and beta cells overlap 12-18% of T2D-associated genome-wide association study candidates. Additionally, ONECUT2 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 'alpha-beta-methylome' ( https://alpha-beta-methylome.serve.scilifelab.se/app/alpha-beta-methylome/ ), a resource exploring T2D, age and sex associations on methylation, highlighting cell-specific epigenetic regulation and dysfunctions contributing to T2D.
NGI Uppsala (SNP&SEQ Technology Platform) [Service]
National Genomics Infrastructure [Service]
PubMed 42032109
DOI 10.1038/s42255-026-01498-9
Crossref 10.1038/s42255-026-01498-9
pmc: PMC13121032
pii: 10.1038/s42255-026-01498-9