What the study found
The study found that human pancreatic alpha and beta cells have many cell-specific DNA methylation differences, and that some of these differences are linked to changes in gene expression. It also identified methylation changes associated with pre-type 2 diabetes and type 2 diabetes in both cell types.
Why the authors say this matters
The authors conclude that these cell-specific epigenetic changes help explain gene regulation and dysfunction contributing to type 2 diabetes. They also present the "alpha-beta-methylome," a resource for exploring associations with type 2 diabetes, age, and sex.
What the researchers tested
The researchers used whole-genome bisulfite sequencing to measure DNA methylation and RNA sequencing to measure gene expression in alpha and beta cells from people with and without type 2 diabetes. They also used CRISPR-dCas9-DNMT3A and CRISPR-dCas9-TET1 epigenetic editing to change methylation at selected sites, and examined ONECUT2 overexpression in beta cells and islets.
What worked and what didn't
They found 22,544 differentially methylated regions in alpha versus beta cells, annotated to 7,975 genes, with about 50% showing differential expression. Increasing INS and TH methylation changed INS, TH, or GCG expression and content, while decreasing GCG methylation also altered GCG expression and content. ONECUT2 overexpression downregulated gene sets affecting insulin secretion and glucose homeostasis, and reduced mitochondrial activity, ATP/ADP ratio, and insulin secretion.
What to keep in mind
The abstract does not describe detailed limitations beyond the available cell-type and study comparisons. It also reports overlap of pre-T2D/T2D-associated methylated regions with 12-18% of T2D-associated genome-wide association study candidates, but does not specify which candidates were functionally confirmed.
Key points
- Alpha and beta cells showed 22,544 differentially methylated regions across 7,975 genes.
- About half of those methylation differences were also associated with differential gene expression.
- CRISPR-based epigenetic editing changed methylation and altered INS, TH, or GCG expression and content in beta cells.
- Pre-T2D/T2D-associated methylated regions overlapped 12-18% of type 2 diabetes genome-wide association study candidates.
- ONECUT2 was epigenetically upregulated in beta cells from people with pre-T2D/T2D and overexpression reduced insulin secretion-related measures.
- The authors provide an "alpha-beta-methylome" resource for exploring methylation associations with type 2 diabetes, age, and sex.
Disclosure
- Research title:
- Cell-specific methylation changes in alpha and beta cells in type 2 diabetes
- Authors:
- Jones K. Ofori, Sabrina Ruhrmann, Axel Lindström, Alexander Perfilyev, Melina Martin, Alexandros Karagiannopoulos, Lucia Scisciola, Katja Kost, Josefine Jönsson, Åsa Nilsson, Boris Kantor, Monika Dudenhöffer‐Pfeifer, Marianne G. Rots, Anna Wendt, Tina Rönn, Lena Eliasson, Karl Bacos, Charlotte Ling
- Institutions:
- Malmö University, Lund University, Science for Life Laboratory, University of Copenhagen, University of Campania "Luigi Vanvitelli", Florida State University, University Medical Center Groningen, University of Groningen
- Publication date:
- 2026-04-24
- OpenAlex record:
- View
- Image credit:
- Photo by Anna Tarazevich on Pexels · Pexels License
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