The Polycomb-dependent epigenome controls β-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 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. Whole islet mRNA profiles of 8-week and 25-week old wild type (WT) and Eed -/- mice (βEedKO) were generated (in triplicates, two replicates for 25-week βEedKO samples). Whole islet ChIP-seq profiles of young mice (8-16 week old) for several histone marks and Pol-II were generated. H3K27ac ChIP was also done in Eed-knockout mice. Please note that the 'wt_mouse_ilets_chromatin_states.paper_colors.bed' file with chromatin states output from EpicSeg (Mammana and Chung, 2015) combining the ChIP-seq data for H3K4me3, H3K27ac, H3K27me3, H3K27me2, H3K27me1, H3K36me3, H2AK119Ub, H3K9me3 and Pol2 together with external available data for H3K4me1, H3K27me3 and H3K9me3 marks [Hoffman et al., 2010; Tennant et al., 2013] and methylation data from young islets [Avrahami et al., 2015]; binSize=200bp