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

Lu TTH, Heyne S, Dror E, Casas E, Leonhardt L, Boenke T, Yang CH, Sagar , Arrigoni L, Dalgaard K, Teperino R, Enders L, Selvaraj M, Ruf M, Raja SJ, Xie H, Boenisch U, Orkin SH, Lynn FC, Hoffman BG, Gruen D, Vavouri T, Lempradl AM, Pospisilik JA (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Cell Metabolism Elsevier (Cell Press)

Book Volume: 27

Pages Range: 1294-1308.e7

Journal Issue: 6

DOI: 10.1016/j.cmet.2018.04.013

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. Lu et al. provide evidence of chromatin dysregulation in type 2 diabetes in mice and humans. Loss of Polycomb silencing in mouse pancreas triggers hyperglycemia-independent dedifferentiation of β cells and diabetes, suggesting a two-hit (chromatin and hyperglycemia) model for loss of β cell identity in diabetes.

Involved external institutions

Max-Planck-Institut für Immunbiologie und Epigenetik (MPI-IE) / Max Planck Institute of Immunobiology and Epigenetics DE Germany (DE) Autonomous University of Barcelona (UAB) / Universitat Autònoma de Barcelona ES Spain (ES) Harvard University US United States (USA) (US) BC Children's Hospital Research Institute CA Canada (CA)

How to cite

APA:

Lu, T.T.-H., Heyne, S., Dror, E., Casas, E., Leonhardt, L., Boenke, T.,... Pospisilik, J.A. (2018). The Polycomb-Dependent Epigenome Controls β Cell Dysfunction, Dedifferentiation, and Diabetes. Cell Metabolism, 27(6), 1294-1308.e7. https://doi.org/10.1016/j.cmet.2018.04.013

MLA:

Lu, Tess Tsai-Hsiu, et al. "The Polycomb-Dependent Epigenome Controls β Cell Dysfunction, Dedifferentiation, and Diabetes." Cell Metabolism 27.6 (2018): 1294-1308.e7.

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