GEO series

SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation.

GSE279619 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 124 samples Submitted 2025/01/17 Platform GPL20301

Summary

SETD2 is the sole epigenetic factor responsible for catalyzing histone 3, lysine 36, tri-methylation (H3K36me3) in mammals. Its role in regulating diverse cellular processes such as RNA splicing, DNA repair, and spurious transcription underlie its broader tumor suppressor function, which has been detailed in a multitude of cancer types. SETD2 mutation, and by extension loss of H3K36me3, promotes the epithelial-mesenchymal transition (EMT) and is clinically associated with adverse outcomes highlighting a therapeutic need to develop targeted therapies against this dangerous mutation. To this end we employed an unbiased genome-wide synthetic lethal screen, which identified another H3K36me writer, NSD1, as a synthetic lethal modifier in SETD2-mutant cells. Confirmation of this synthetic lethal interaction was performed via modeling in isogenic clear cell renal cell carcinoma (ccRCC ) cell lines. Depletion of NSD1 using a CRISPRi targeting approach promoted the loss of SETD2-mutant cells coincident with elevated DNA damage and apoptosis. Surprisingly, only suppression of NSD1, and not the related H3K36-methyltransferases NSD2 or NSD3, promoted synthetic lethality (SL) in these models. Further investigation of H3K36me2 targeting by NSD1 and NSD2 respectively highlight the independent functions of these epigenetic writers. Furthermore, as a proof-of-principle we demonstrate the therapeutic feasibility of targeting this synthetic lethal interaction by recapitulating the phenotype using a first-of-its kind pharmacologic inhibitor against NSD1 (BT5). Notably, these findings unify unbiased genome-wide screening approaches with the latest genetic and pharmacologic modeling methodologies to reveal an entirely novel epigenetic approach in the advancement of individualized therapies for the treatment of SETD2-mutant cancer.

Published in

SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation

Wagner RT, Hlady RA, Pan X et al. · Genome biology 2025 · PMID 39910618 · doi:10.1186/s13059-025-03483-z

This dataset

Open GSE279619 in finder → Find more human ChIP / ATAC / CUT&Tag datasets →

Download

Direct links to NCBI, no account and no request form: the whole study as GSE279619_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 124 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 PRJNA1173660 and SRA study SRP538934. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 39910618) ↗

Study design

40 conditions, each sampled once — no replicated groups

Read from the first 40 of 124 sample titles: 40 distinct titles with little repetition. Check it against the sample list below before relying on it.

Similar datasets

Search all human ChIP / ATAC / CUT&Tag datasets in GEO →

Share this dataset

Metadata from NCBI GEO, cached and refreshed periodically — the NCBI page above is authoritative. Downloads link straight to NCBI/ENA; nothing is proxied through BioTransfer.