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

TY - JOUR

T1 - Islet cells share promoter hypomethylation independently of expression, but exhibit cell-type-specific methylation in enhancers

AU - Neiman, Daniel

AU - Moss, Joshua

AU - Hecht, Merav

AU - Magenheim, Judith

AU - Piyanzin, Sheina

AU - Shapiro, A M James

AU - de Koning, Eelco J P

AU - Razin, Aharon

AU - Cedar, Howard

AU - Shemer, Ruth

AU - Dor, Yuval

N1 - Copyright © 2017 the Author(s). Published by PNAS.

PY - 2017/12/19

Y1 - 2017/12/19

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1073/pnas.1713736114

DO - 10.1073/pnas.1713736114

M3 - Article

C2 - 29203669

SN - 0027-8424

VL - 114

SP - 13525

EP - 13530

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 51

ER -