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

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.