The NSD2/WHSC1/MMSET methyltransferase prevents cellular senescence‐associated epigenomic remodeling

Senescent cells may possess the intrinsic programs of metabolic and epigenomic remodeling, but the molecular mechanism remains to be clarified. Using an RNAi‐based screen of chromatin regulators, we found that knockdown of the NSD2/WHSC1/MMSET methyltransferase induced cellular senescence that augmented mitochondrial mass and oxidative phosphorylation in primary human fibroblasts. Transcriptome analysis showed that loss of NSD2 downregulated the expression of cell cycle‐related genes in a retinoblastoma protein (RB)‐mediated manner. Chromatin immunoprecipitation analyses further revealed that NSD2 was enriched at the gene bodies of actively transcribed genes, including cell cycle‐related genes, and that loss of NSD2 decreased the levels of histone H3 lysine 36 trimethylation (H3K36me3) at these gene loci. Consistent with these findings, oncogene‐induced or replicative senescent cells showed reduced NSD2 expression together with lower H3K36me3 levels at NSD2‐enriched genes. In addition, we found that NSD2 gene was upregulated by serum stimulation and required for the induction of cell cycle‐related genes. Indeed, in both mouse and human tissues and human cancer cell lines, the expression levels of NSD2 were positively correlated with those of cell cycle‐related genes. These data reveal that NSD2 plays a pivotal role in epigenomic maintenance and cell cycle control to prevent cellular senescence.