論文

査読有り 国際誌
2020年6月22日

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

Aging cell
  • Hiroshi Tanaka
  • ,
  • Tomoka Igata
  • ,
  • Kan Etoh
  • ,
  • Tomoaki Koga
  • ,
  • Shin-Ichiro Takebayashi
  • ,
  • Mitsuyoshi Nakao

記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1111/acel.13173

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.

リンク情報
DOI
https://doi.org/10.1111/acel.13173
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32573059
ID情報
  • DOI : 10.1111/acel.13173
  • PubMed ID : 32573059

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