The NSD2/WHSC1/MMSET methyltransferase prevents cellular senescence-associated epigenomic remodeling
The NSD2/WHSC1/MMSET methyltransferase prevents cellular senescence-associated epigenomic remodeling
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DOI：
10.1111/acel.13173
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发表时间：
2020-06-22
期刊：
影响因子：
7.8
通讯作者：
Nakao, Mitsuyoshi
中科院分区：
文献类型：
--
作者：
Tanaka, Hiroshi;Igata, Tomoka;Nakao, Mitsuyoshi
衰老细胞可能具有代谢和表观基因组重构的内在程序，但其分子机制仍有待阐明。使用基于RNAi的染色质调节剂筛选，我们发现NSD 2/WHSC 1/MMSET甲基转移酶的敲低诱导细胞衰老，这增加了原代人成纤维细胞中的线粒体质量和氧化磷酸化。转录组分析表明，NSD 2的损失下调视网膜母细胞瘤蛋白（RB）介导的方式中的细胞周期相关基因的表达。染色质免疫沉淀分析进一步揭示，NSD 2富集在活跃转录基因的基因体中，包括细胞周期相关基因，并且NSD 2的缺失降低了这些基因位点的组蛋白H3赖氨酸36三甲基化（H3 K36 me 3）水平。与这些发现一致，癌基因诱导的或复制性衰老细胞显示NSD 2表达降低以及NSD 2富集基因的H3 K36 me 3水平降低。另外，我们还发现NSD 2基因在血清刺激下表达上调，并参与细胞周期相关基因的诱导。事实上，在小鼠和人类组织以及人类癌细胞系中，NSD 2的表达水平与细胞周期相关基因的表达水平呈正相关。这些数据表明，NSD 2在表观基因组维持和细胞周期控制中起着关键作用，以防止细胞衰老。
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 thatNSD2gene 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 ofNSD2were 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.