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Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes

Ofori, Jones K LU ; Ruhrmann, Sabrina LU ; Lindström, Axel LU orcid ; Perfilyev, Alexander LU orcid ; Martin, Melina LU ; Karagiannopoulos, Alexandros LU orcid ; Scisciola, Lucia LU ; Kost, Katja ; Jönsson, Josefine LU orcid and Nilsson, Åsa LU , et al. (2026) In Nature Metabolism
Abstract

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... (More)

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.

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Contribution to journal
publication status
epub
subject
in
Nature Metabolism
publisher
Springer Nature
external identifiers
  • pmid:42032109
ISSN
2522-5812
DOI
10.1038/s42255-026-01498-9
language
English
LU publication?
yes
additional info
© 2026. The Author(s).
id
39b6da89-5f3d-4768-8651-77037aa9869e
date added to LUP
2026-04-27 09:04:55
date last changed
2026-04-28 03:29:54
@article{39b6da89-5f3d-4768-8651-77037aa9869e,
  abstract     = {{<p>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.</p>}},
  author       = {{Ofori, Jones K and Ruhrmann, Sabrina and Lindström, Axel and Perfilyev, Alexander and Martin, Melina and Karagiannopoulos, Alexandros and Scisciola, Lucia and Kost, Katja and Jönsson, Josefine and Nilsson, Åsa and Kantor, Boris and Rots, Marianne G and Dudenhöffer-Pfeifer, Monika and Wendt, Anna and Rönn, Tina and Eliasson, Lena and Bacos, Karl and Ling, Charlotte}},
  issn         = {{2522-5812}},
  language     = {{eng}},
  month        = {{04}},
  publisher    = {{Springer Nature}},
  series       = {{Nature Metabolism}},
  title        = {{Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes}},
  url          = {{http://dx.doi.org/10.1038/s42255-026-01498-9}},
  doi          = {{10.1038/s42255-026-01498-9}},
  year         = {{2026}},
}