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

Publication date: Available online 10 May 2018
Source:Cell Metabolism
Author(s): Tess Tsai-Hsiu Lu, Steffen Heyne, Erez Dror, Eduard Casas, Laura Leonhardt, Thorina Boenke, Chih-Hsiang Yang, Sagar, Laura Arrigoni, Kevin Dalgaard, Raffaele Teperino, Lennart Enders, Madhan Selvaraj, Marius Ruf, Sunil J. Raja, Huafeng Xie, Ulrike Boenisch, Stuart H. Orkin, Francis C. Lynn, Brad G. Hoffman, Dominic Grün, Tanya Vavouri, Adelheid M. Lempradl, J. Andrew Pospisilik
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.

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Teaser

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.


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