The NSD2/WHSC1/MMSET methyltransferase prevents cellular senescence-associated epigenomic remodeling.
Hiroshi TanakaTomoka IgataKan EtohTomoaki KogaShin-Ichiro TakebayashiMitsuyoshi NakaoPublished in: Aging cell (2020)
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.
Keyphrases
- cell cycle
- genome wide
- endothelial cells
- cell proliferation
- high glucose
- dna damage
- poor prognosis
- genome wide identification
- induced apoptosis
- gene expression
- dna methylation
- copy number
- transcription factor
- cell cycle arrest
- induced pluripotent stem cells
- oxidative stress
- diabetic rats
- pluripotent stem cells
- squamous cell carcinoma
- public health
- high throughput
- signaling pathway
- papillary thyroid
- big data
- data analysis