Hoetker, MichaelYagi, MasakiDi Stefano, BrunoLangerman, JustinCristea, SimonaWong, Lai PingHuebner, Aaron JCharlton, JocelynDeng, WeixianHaggerty, ChuckSadreyev, Ruslan IMeissner, AlexanderMichor, FranziskaPlath, KathrinHochedlinger, Konrad2023-08-222023-07-17Hoetker, Michael, Masaki Yagi, Bruno Di Stefano, Justin Langerman, Simona Cristea, Lai Ping Wong, Aaron J Huebner et al. "H3K36 methylation maintains cell identity by regulating opposing lineage programmes." Nat Cell Biol 25, no. 8 (2023): 1121-1134. DOI: 10.1038/s41556-023-01191-z1465-73921476-4679https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37376887The epigenetic mechanisms that maintain differentiated cell states remain largely unexplored. Here, we employed histone mutants to uncover a crucial role for H3K36-methylation in the maintenance of cell identities across diverse developmental contexts. Focusing on the experimental induction of pluripotency, we show that H3K36M-mediated depletion of H3K36-methylation endows fibroblasts with a plastic state poised to acquire pluripotency in nearly all cells. At a cellular level, H3K36M facilitates epithelial plasticity by rendering fibroblasts insensitive to TGF signals. At a molecular level, H3K36M enables the decommissioning of mesenchymal enhancers and the parallel activation of epithelial/stem cell enhancers. This enhancer rewiring is Tet-dependent and redirects Sox2 from promiscuous somatic to pluripotency targets. Our findings reveal a previously unappreciated dual role for H3K36-methylation in the maintenance of cell identity by integrating a crucial developmental pathway into sustained expression of cell type-specific programs, and by opposing the expression of alternative lineage programs through enhancer methylation.en-USCell BiologyJournal Article2023-08-2210.1038/s41556-023-01191-z