The Polycomb-Dependent Epigenome Controls beta 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, HF; Boenisch, U; Orkin, SH; Lynn, FC; Hoffman, BG; Grun, D; Vavouri, T; Lempradl, AM; Pospisilik, JA


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 beta 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. beta 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 beta cell transcriptional regulation and identifies PRC2 as necessary for long-term maintenance of beta cell identity. Importantly, the data suggest a two-hit (chromatin and hyperglycemia) model for loss of beta cell identity in diabetes.

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