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.
['Tanaka|Hiroshi|H|', 'Igata|Tomoka|T|', 'Etoh|Kan|K|', 'Koga|Tomoaki|T|', 'Takebayashi|Shin-Ichiro|SI|', 'Nakao|Mitsuyoshi|M|0000-0002-2196-8673']
D000818:Animals D016922:Cellular Senescence D057890:Epigenomics D011495:Histone-Lysine N-Methyltransferase D006801:Humans D008297:Male D008780:Methyltransferases D051379:Mice D012097:Repressor Proteins
NSD2/WHSC1/MMSET senescence-associated epigenomic remodeling retinoblastoma cell cycle control H3K36 methylation senescence-associated metabolic remodeling