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.
|Original language||American English|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 19 Dec 2017|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank S. Efrat for the gift of αTC and Min6 cells. This work was funded by grants from the NIH β-Cell Biology Consortium (“MAPLE”, VUMC38149), the Human Islet Research Network, European Union FP7 Program (Grant 241883), the European Research Council (BetaToBeta, STG260685), the Juvenile Diabetes Research Foundation, the Britain–Israel Research and Academic Exchange, the Helmsley Trust, Dutch friends of Hebrew University, the DON Foundation, and the Israel Science Foundation (41.11).
- DNA methylation