Pluto Biosciences, Inc

GSE110648: The Polycomb-dependent epigenome controls -cell dysfunction, dedifferentiation and diabetes

Bulk RNA sequencing

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. SOURCE: Steffen Heyne ( - Max Planck Institute of Immunobiology and Epigenetics

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