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Abstract:
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.
