Islet cells share promoter hypomethylation independently of expression, but exhibit cell-type-specific methylation in enhancers.
DNA methylation at promoters is an important determinant of gene expression. Earlier studies suggested that the insulin gene promoter is uniquely unmethylated in insulin-expressing pancreatic β-cells, providing a classic example of this paradigm. Here we show that islet cells expressing insulin, glucagon, or somatostatin share a lack of methylation at the promoters of the insulin and glucagon genes. This is achieved by rapid demethylation of the insulin and glucagon gene promoters during differentiation of Neurogenin3+ embryonic endocrine progenitors, regardless of the specific endocrine cell-type chosen. Similar methylation dynamics were observed in transgenic mice containing a human insulin promoter fragment, pointing to the responsible cis element. Whole-methylome comparison of human α- and β-cells revealed generality of the findings: genes active in one cell type and silent in the other tend to share demethylated promoters, while methylation differences between α- and β-cells are concentrated in enhancers. These findings suggest an epigenetic basis for the observed plastic identity of islet cell types, and have implications for β-cell reprogramming in diabetes and diagnosis of β-cell death using methylation patterns of circulating DNA.
['Neiman|Daniel|D|', 'Moss|Joshua|J|', 'Hecht|Merav|M|', 'Magenheim|Judith|J|', 'Piyanzin|Sheina|S|', 'Shapiro|A M James|AMJ|', 'de Koning|Eelco J P|EJP|', 'Razin|Aharon|A|', 'Cedar|Howard|H|', 'Shemer|Ruth|R|0000-0003-0625-475X', 'Dor|Yuval|Y|']
D000818:Animals D002454:Cell Differentiation D002460:Cell Line D002478:Cells, Cultured D019175:DNA Methylation D004742:Enhancer Elements, Genetic D044127:Epigenesis, Genetic D050416:Glucagon-Secreting Cells D006801:Humans D050417:Insulin-Secreting Cells D051379:Mice D008813:Mice, Inbred ICR D011401:Promoter Regions, Genetic
islets DNA methylation β-cells epigenetic development