Scientists pinpoint epigenetic switches that trigger type 2 diabetes
Researchers have identified how chemical modifications to DNA in pancreatic cells shut down insulin production, opening a path to new diabetes treatments. The findings map which genes are silenced in diabetes and show these changes can be reversed using gene-editing tools, potentially transforming how the disease is managed.
Originaltitel: Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes
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 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.