Muscle-Specific Histone H3K36 Dimethyltransferase SET-18 Shortens Lifespan of Caenorhabditis elegans by Repressing daf-16a Expression
Muscle-Specific Histone H3K36 Dimethyltransferase SET-18 Shortens Lifespan of Caenorhabditis elegans by Repressing daf-16a Expression
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肌肉特异性组蛋白 H3K36 二甲基转移酶 SET-18 通过抑制 daf-16a 表达来缩短秀丽隐杆线虫的寿命。
DOI：
10.1016/j.celrep.2018.02.029
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发表时间：
2018
期刊：
影响因子：
8.8
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Su L;Li H;Huang C;Zhao T;Zhang Y;Ba X;Li Z;Zhang Y;Huang B;Lu J;Zhao Y;Li X
越来越多的证据表明，组蛋白甲基化是一种典型的表观遗传标记，在衰老过程中对基因表达调控至关重要。据报道，蠕虫和酵母中组蛋白H3（H3 K36 me 3）上赖氨酸36的三甲基化减少会缩短寿命。H3 K36 me 2在衰老中的作用尚不清楚。在这项研究中，我们确定秀丽隐杆线虫SET-18是一个组蛋白H3 K36二甲基转移酶。SET-18缺失延长了寿命，增加了氧化应激抗性，这取决于胰岛素/IGF途径中的daf-16活性。Inset-18突变体中，daf-16亚型（daf-16 a）的转录特异性上调。因此，观察到H3 K36 me 2 ondaf-16 a启动子的减少。SET-18的肌肉特异性表达在老年蠕虫（第7天和第11天）中增加，归因于总体H3 K36 me 2的升高和daf-16 a表达的抑制。因此，寿命缩短。这些发现表明，由组织特异性H3 K36二甲基转移酶介导的染色质阻遏可能对寿命有害，并可能对人类年龄相关疾病产生影响。
Mounting evidence shows that histone methylation, a typical epigenetic mark, is crucial for gene expression regulation during aging. Decreased trimethylation of Lys 36 on histone H3 (H3K36me3) in worms and yeast is reported to shorten lifespan. The function of H3K36me2 in aging remains unclear. In this study, we identifiedCaenorhabditis elegansSET-18 as a histone H3K36 dimethyltransferase. SET-18 deletion extended lifespan and increased oxidative stress resistance, dependent ondaf-16activity in the insulin/IGF pathway. Inset-18mutants, transcription ofdaf-16isoforma(daf-16a) was specifically upregulated. Accordingly, a decrease in H3K36me2 ondaf-16apromoter was observed. Muscle-specific expression of SET-18 increased in aged worms (day 7 and day 11), attributable to elevation of global H3K36me2 and inhibition ofdaf-16aexpression. Consequently, longevity was shortened. These findings suggested that chromatic repression mediated by tissue-specific H3K36 dimethyltransferase might be detrimental to lifespan and may have implications in human age-related diseases.