| First Author | Dror E | Year | 2023 |
| Journal | Cell Metab | Volume | 35 |
| Issue | 5 | Pages | 821-836.e7 |
| PubMed ID | 36948185 | Mgi Jnum | J:335545 |
| Mgi Id | MGI:7470600 | Doi | 10.1016/j.cmet.2023.03.008 |
| Citation | Dror E, et al. (2023) Epigenetic dosage identifies two major and functionally distinct beta cell subtypes. Cell Metab 35(5):821-836.e7 |
| abstractText | The mechanisms that specify and stabilize cell subtypes remain poorly understood. Here, we identify two major subtypes of pancreatic beta cells based on histone mark heterogeneity (beta(HI) and beta(LO)). beta(HI) cells exhibit approximately 4-fold higher levels of H3K27me3, distinct chromatin organization and compaction, and a specific transcriptional pattern. beta(HI) and beta(LO) cells also differ in size, morphology, cytosolic and nuclear ultrastructure, epigenomes, cell surface marker expression, and function, and can be FACS separated into CD24(+) and CD24(-) fractions. Functionally, beta(HI) cells have increased mitochondrial mass, activity, and insulin secretion in vivo and ex vivo. Partial loss of function indicates that H3K27me3 dosage regulates beta(HI)/beta(LO) ratio in vivo, suggesting that control of beta cell subtype identity and ratio is at least partially uncoupled. Both subtypes are conserved in humans, with beta(HI) cells enriched in humans with type 2 diabetes. Thus, epigenetic dosage is a novel regulator of cell subtype specification and identifies two functionally distinct beta cell subtypes. |
