Islet cells share promoter hypomethylation independently of expression, but exhibit cell-type-specific methylation in enhancers
| Autor: | Sheina Piyanzin, Yuval Dor, Ruth Shemer, A. M. James Shapiro, Judith Magenheim, Howard Cedar, Joshua Moss, Aharon Razin, Merav Hecht, Eelco J.P. de Koning, Daniel Neiman |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
endocrine system Medical Sciences endocrine system diseases β-cells 030209 endocrinology & metabolism Biology Development Cell Line Epigenesis Genetic Mice 03 medical and health sciences 0302 clinical medicine Insulin-Secreting Cells Gene expression Journal Article Animals Humans Epigenetics Promoter Regions Genetic Enhancer General Gene development Cells Cultured islets Mice Inbred ICR Multidisciplinary DNA methylation Epigenetic Cell Differentiation Promoter Methylation Biological Sciences Cell biology Enhancer Elements Genetic 030104 developmental biology Glucagon-Secreting Cells beta-cells Islets Reprogramming epigenetic |
| Zdroj: | Proceedings of the National Academy of Sciences, 114(51), 13525-13530 Proceedings of the National Academy of Sciences of the United States of America, 114(51), 13525 Proceedings of the National Academy of Sciences Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, 114(51), 13525-13530. National Academy of Sciences |
| ISSN: | 0027-8424 |
| Popis: | Significance We have studied the dynamics of DNA methylation in pancreatic α- and β-cells and reached surprising insights into the establishment of islet cell identity. Different islet cell types share lack of methylation in cell-type–specific gene promoters, while DNA methylation differences between islet cell types are concentrated in enhancer regions. The findings support the fundamental role of enhancer methylation in determining cell identity, and have implications for the understanding of islet cell plasticity in diabetes. 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. |
| Databáze: | OpenAIRE |
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