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H3K36 methylation maintains cell identity by regulating opposing lineage programs

ABSTRACT: While epigenetic regulation in early development and differentiation is relatively well-characterized, the precise mechanisms that subsequently maintain specialized cell states remain largely unexplored. Here, we employed histone H3.3 mutants to uncover a crucial role for H3K36 methylation in the maintenance of cell identities across diverse developmental contexts. Focusing on the experimentally induced conversion of fibroblasts to pluripotent stem cells, we show that H3K36M-mediated disruption of H3K36 methylation endowed reprogramming intermediates with a plastic state poised to acquire pluripotency in nearly all cells. At a cellular level, H3K36M rendered mesenchymal cells insensitive to TGF signals and thus facilitated epithelial plasticity. At a molecular level, H3K36M led to the downregulation of mesenchymal genes by depleting H3K36me2 and H3K27ac at associated enhancers. In parallel, H3K36M led to the upregulation of epithelial and stem cell genes by enabling enhancer accessibility and hypomethylation. Mechanistically, we found that Tet-dependent demethylation uncouples pluripotency enhancer activation from somatic enhancer decommissioning in K36M cells. This dynamic switch of enhancer activities redirects Sox2 binding from promiscuous somatic targets to bona fide stem cell targets crucial for the establishment of the pluripotency network. Together, our findings reveal a dual role for H3K36 methylation in the maintenance of cell identity by integrating a key developmental pathway into sustained expression of cell type-specific programs, and by opposing the expression of alternative lineage programs through continual enhancer methylation. Our results provide crucial insight into the impact of dynamic H3K36 methylation patterns on physiological and pathological cell fate transitions, including development, tissue regeneration and cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE203536 | GEO | 2023/02/04

REPOSITORIES: GEO

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Project description:Histone tails are post-translationally modified at multiple sites, including Lys36 on histone H3 (H3K36). The H3K36 methylation has been shown to associate with the transcription of active euchromatin, alternative splicing, DNA repair and recombination. However, the role of H3K36 methylation during cell differentiation is still obscure.Previous investigations found that a site specific Lys-to-Met mutation on histones can serve as an inhibitor of this site specific methyltransferases to repress global methylation on that lysine of histones. In this study we usedH3K36 Lys-to-Met mutant (H3K36M) as a tool to investigaterole of H3K36 methylation in our cell differentiation system. Expression of H3K36M repressed global H3K36 methylation but increased H3K27me3 as previously reported. On our cell differentiation system, H3K36M suppressed adipogenesis and myogenesis. Our pioneer RNA-seqstudy further showed that H3K36M repressed the expression of master regulator genes. Here, we did ChIP-seq of several histone modifications to further explore the changes on the epigenome by expression of H3K36M. Interestingly, on some important master regulator genes loci, the repressive marker H3K27me3 increased significantly, correlated with the repression on their expression. The H3K36M decreases global H3K36 di- and tri-methylation. To clarify which H3K36 methyltransferase is important for cell differentiation, we knocked down H3K36 di-methyltransferases Nsd1 and Nsd2, H3K36 tri-methyltransferase Setd2 separately. Nsd2 knockdown, but not Nsd1 or Setd2,can phenocopythe adipogenesis defect in H3K36M expressed cells.Comparing in RNA-seq results, Nsd2 knockdown cells showed similar gene expression profile with H3K36M expressed cells in adipogenesis. These suggest that Nsd2-mediated H3K36me2 plays an important role in adipogenesis.To study the role of H3K36 methylation in vivo, we generated an aP2 promoter driven H3K36M expressed transgenic mouse (Tg), to express H3K36M specifically in adipose tissue. The Tg mice showedsignificant dysfunction in both white and brown adipose tissues. Their fat tissues gene expression profile changed significantly. All of these indicate that H3K36 methylation is important for adipose tissue developmentin vivo.Together, our comprehensive studies provide novel insights into dynamics of H3K36 methylation and its important role in transcriptional regulation of cell differentiation and mouse fat tissue development.

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H3K36 methylation maintains cell identity by regulating opposing lineage programs

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