title: Whole-Genome Bisulfite Sequencing of Human Pancreatic Islets Reveals Novel Differentially Methylated Regions in Type 2 Diabetes Pathogenesis.
abstract: Current knowledge about the role of epigenetics in type 2 diabetes (T2D) remains limited. Only a few studies have investigated DNA methylation of selected candidate genes or a very small fraction of genomic CpG sites in human pancreatic islets, the tissue of primary pathogenic importance for diabetes. Our aim was to characterize the whole-genome DNA methylation landscape in human pancreatic islets, to identify differentially methylated regions (DMRs) in diabetic islets, and to investigate the function of DMRs in islet biology. Here, we performed whole-genome bisulfite sequencing, which is a comprehensive and unbiased method to study DNA methylation throughout the genome at a single nucleotide resolution, in pancreatic islets from donors with T2D and control subjects without diabetes. We identified 25,820 DMRs in islets from individuals with T2D. These DMRs cover loci with known islet function, e.g.,PDX1,TCF7L2, andADCY5Importantly, binding sites previously identified by ChIP-seq for islet-specific transcription factors, enhancer regions, and different histone marks were enriched in the T2D-associated DMRs. We also identified 457 genes, includingNR4A3,PARK2,PID1,SLC2A2, andSOCS2, that had both DMRs and significant expression changes in T2D islets. To mimic the situation in T2D islets, candidate genes were overexpressed or silenced in cultured β-cells. This resulted in impaired insulin secretion, thereby connecting differential methylation to islet dysfunction. We further explored the islet methylome and found a strong link between methylation levels and histone marks. Additionally, DNA methylation in different genomic regions and of different transcript types (i.e., protein coding, noncoding, and pseudogenes) was associated with islet expression levels. Our study provides a comprehensive picture of the islet DNA methylome in individuals with and without diabetes and highlights the importance of epigenetic dysregulation in pancreatic islets and T2D pathogenesis.
authors.affiliation: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden.
authors.forename: Petr
authors.initials: P
authors.lastname: Volkov
authors.affiliation: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Bacos
authors.affiliation: Islet Cell Exocytosis Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden.
authors.forename: Jones K
authors.initials: JK
authors.lastname: Ofori
authors.affiliation: Islet Cell Exocytosis Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden.
authors.forename: Jonathan Lou S
authors.initials: JL
authors.lastname: Esguerra
authors.affiliation: Islet Cell Exocytosis Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden.
authors.forename: Lena
authors.identifier: 0000-0002-6467-5029
authors.initials: L
authors.lastname: Eliasson
authors.affiliation: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden.
authors.forename: Tina
authors.initials: T
authors.lastname: Rönn
authors.affiliation: Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden charlotte.ling@med.lu.se.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ling
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D019175:DNA Methylation / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017422:Sequence Analysis, DNA
chemical_list: D007328:Insulin