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


ABSTRACT: 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.

SUBMITTER: Tanaka H 

PROVIDER: S-EPMC7433007 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Tanaka Hiroshi H   Igata Tomoka T   Etoh Kan K   Koga Tomoaki T   Takebayashi Shin-Ichiro SI   Nakao Mitsuyoshi M  

Aging cell 20200622 7


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 retino  ...[more]

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