| First Author | Lu TT | Year | 2018 |
| Journal | Cell Metab | Volume | 27 |
| Issue | 6 | Pages | 1294-1308.e7 |
| PubMed ID | 29754954 | Mgi Jnum | J:263265 |
| Mgi Id | MGI:6163913 | Doi | 10.1016/j.cmet.2018.04.013 |
| Citation | Lu TT, et al. (2018) The Polycomb-Dependent Epigenome Controls beta Cell Dysfunction, Dedifferentiation, and Diabetes. Cell Metab 27(6):1294-1308.e7 |
| abstractText | 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. |
