Format

Send to

Choose Destination
Cell Metab. 2018 Jun 5;27(6):1294-1308.e7. doi: 10.1016/j.cmet.2018.04.013. Epub 2018 May 10.

The Polycomb-Dependent Epigenome Controls β Cell Dysfunction, Dedifferentiation, and Diabetes.

Author information

1
Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
2
Program for Predictive and Personalized Medicine of Cancer (PMPPC), Institute Germans Trias i Pujol, UAB, Badalona 08916, Spain.
3
Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany; Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
5
Diabetes Research Program, BC Children's Hospital Research Institute, A4-184, 950 West 28 Avenue, Vancouver, BC V5Z 4H4, Canada.
6
Program for Predictive and Personalized Medicine of Cancer (PMPPC), Institute Germans Trias i Pujol, UAB, Badalona 08916, Spain; Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias i Pujol, Badalona 08916, Spain.
7
Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany. Electronic address: pospisilik@ie-freiburg.mpg.de.

Abstract

To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combine deep epigenome mapping with single-cell transcriptomics to mine for evidence of chromatin dysregulation in type 2 diabetes. We find two chromatin-state signatures that track β cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-silenced domains and loss of expression at an epigenomically unique class of lineage-defining genes. β cell-specific Polycomb (Eed/PRC2) loss of function in mice triggers diabetes-mimicking transcriptional signatures and highly penetrant, hyperglycemia-independent dedifferentiation, indicating that PRC2 dysregulation contributes to disease. The work provides novel resources for exploring β cell transcriptional regulation and identifies PRC2 as necessary for long-term maintenance of β cell identity. Importantly, the data suggest a two-hit (chromatin and hyperglycemia) model for loss of β cell identity in diabetes.

KEYWORDS:

Eed; Polycomb; cell identity; chromatin; complex diseases; de-differentiation; diabetes; epigenetic; type 2 diabetes; β cells

Comment in

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center