Hoetker MS, Yagi M, Di Stefano B, Langerman J, Cristea S, Wong LP, Huebner AJ, Charlton J, Deng W, Haggerty C, Sadreyev RI, Meissner A, Michor F, Plath K, Hochedlinger K. 2023. H3K36 methylation maintains cell identity by regulating opposing lineage programmes. Nature cell biology. 25(8):1121-1134. Pubmed: 37460697 DOI:10.1038/s41556-023-01191-z


The epigenetic mechanisms that maintain differentiated cell states remain incompletely understood. 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 TGFβ 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 programmes, and by opposing the expression of alternative lineage programmes through enhancer methylation.
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.

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Franziska Michor uses the tools of theoretical evolutionary biology, applied mathematics, statistics, and computational biology to address important questions in cancer research.

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