GEO series

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

GSE274361 Homo sapiens; Mus musculus Genome binding/occupancy profiling by high throughput sequencing 81 samples Submitted 2025/10/23 Platform GPL20301Platform GPL21103

Summary

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.

Published in

H3K36 Methylation as a Guardian of Epigenome Integrity

Padilla R, Shipman GA, Horth C et al. · Nature communications 2025 · PMID 41381501 · doi:10.1038/s41467-025-66365-9

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Direct links to NCBI, no account and no request form: the whole study as GSE274361_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 81 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA1146044 and SRA study SRP525179. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 41381501) ↗

Study design

40 conditions, each sampled once — no replicated groups

Read from the first 40 of 81 sample titles: 40 distinct titles with little repetition. Check it against the sample list below before relying on it.

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