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

Lu, Tess Tsai-Hsiu; Heyne, Steffen; Dror, Erez; Casas, Eduard; Leonhardt, Laura; Boenke, Thorina; Yang, Chih-Hsiang; Sagar, Sagar; Arrigoni, Laura; Dalgaard, Kevin; Teperino, Raffaele; Enders, Lennart; Selvaraj, Madhan; Ruf, Marius; Raja, Sunil J.; Xie, Huafeng; Boenisch, Ulrike; Orkin, Stuart H.; Lynn, Francis C.; Hoffman, Brad G.; Grün, Dominic; Vavouri, Tanya; Lempradl, Adelheid M.; Pospisilik, J. Andrew

doi:doi.org/10.1016/j.cmet.2018.04.013

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

MPS-Authors

Lu, Tess Tsai-Hsiu
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Heyne, Steffen
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Dror, Erez
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Leonhardt, Laura
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Boenke, Thorina
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Yang, Chih-Hsiang
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Sagar, Sagar
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Arrigoni, Laura
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Dalgaard, Kevin
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Teperino, Raffaele
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Enders, Lennart
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Selvaraj, Madhan
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Ruf, Marius
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Raja, Sunil J.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Boenisch, Ulrike
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Grün, Dominic
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lempradl, Adelheid M.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Pospisilik, J. Andrew
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Lu, T.-T.-H., Heyne, S., Dror, E., Casas, E., Leonhardt, L., Boenke, T., et al. (2018). The Polycomb-Dependent Epigenome Controls β Cell Cysfunction, Dedifferentiation, and Diabetes. Cell Metabolism, 15, 1294-1308. doi:doi.org/10.1016/j.cmet.2018.04.013.

Cite as: https://hdl.handle.net/21.11116/0000-0001-F751-D

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.