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

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

SUBMITTER: Lu TT 

PROVIDER: S-EPMC5989056 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature