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H3K36 Methylation - a Guardian of Epigenome Integrity [ChIP-Seq]

ABSTRACT: H3K36 methylation is a key epigenetic mark with critical roles in development and disease, yet its genome-wide functions remain incompletely understood. Here, we systematically dissect the role of H3K36 methylation using a series of CRISPR-engineered mouse mesenchymal stem cell lines with progressive knockouts of the five H3K36 methyltransferases: NSD1, NSD2, NSD3, SETD2 and ASH1L—culminating in quintuple knockout (QuiKO) cells entirely lacking H3K36me2/3. We demonstrate that H3K36me2 enriched at active cis-regulatory elements predominantly influences enhancer activity and supports the expression of enhancer-dependent genes. Within gene bodies, loss of H3K36me2/3 permits invasion by the repressive H3K27me2/3 modifications, thereby disrupting transcriptional fidelity. Unexpectedly, we uncover a previously undescribed relationship between H3K36me and H3K9me3: upon H3K36me2 depletion, SUV39H1-mediated H3K9me3 redistributes from large constitutive heterochromatic domains into euchromatin, leading to widespread epigenome restructuring and transcriptional changes. This redistribution is accompanied by a collapse of 3D genome organization, including weakened compartment boundaries and a profound loss of long-range interactions. Finally, we validate key findings in two human HNSCC cell lines overexpressing the H3K36M oncohistone, highlighting the conserved role of H3K36 methylation in maintaining epigenome integrity across species and cell types, and providing further mechanistic insights into the downstream consequences of this oncogenic mutation. Together, these data reveal that H3K36me is essential not only for local gene regulation but also for safeguarding the higher-order structure and functional balance of the genome.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE274361 | GEO | 2025/10/23

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 - a Guardian of Epigenome Integrity [ChIP-Seq]

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