Islet cells share promoter hypomethylation independently of expression, but exhibit cell-type-specific methylation in enhancers

Daniel Neiman, Joshua Moss, Merav Hecht, Judith Magenheim, Sheina Piyanzin, A M James Shapiro, Eelco J P de Koning, Aharon Razin, Howard Cedar, Ruth Shemer, Yuval Dor

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)13525-13530
Aantal pagina's6
TijdschriftProceedings of the National Academy of Sciences of the United States of America
Volume114
Nummer van het tijdschrift51
DOI's
StatusGepubliceerd - 19 dec 2017

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