Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans.
Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans.
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衰老的可塑性表明，长寿可能是通过染色质状态的特定改变来控制的。染色质和衰老之间的联系主要集中在Sir 2家族的组蛋白去乙酰化，但对其他组蛋白修饰在长寿中的作用知之甚少。组蛋白甲基化在哺乳动物的发育和维持干细胞多能性中起着至关重要的作用。组蛋白甲基化的调节剂与蠕虫和苍蝇的衰老有关，但对其作用和作用机制的表征有限。在这里，我们确定了ASH-2三胸复合物，三甲基化组蛋白H3的赖氨酸4（H3 K4），作为一个调节器的寿命在C。elegans在可育蠕虫中的定向RNAi筛选。在ASH-2复合物成员中的防御-ASH-2本身、WDR-5和H3 K4甲基转移酶SET-2延长蠕虫寿命。相反，H3 K4去甲基化酶RBR-2是正常寿命所必需的，这与过量的H3 K4三甲基化（与活性染色质相关的标记）对寿命有害的观点一致。由ASH-2复合物缺陷诱导的寿命延长需要存在完整的成体生殖系和连续产生成熟卵子。ASH-2和RBR-2在生殖系中起作用，至少部分地调节寿命并控制一组参与寿命决定的基因。这些结果表明，索马的寿命是由一个H3 K4甲基转移酶/脱甲基酶复合物在C.秀丽隐杆线虫生殖系
The plasticity of aging suggests that longevity may be controlled epigenetically by specific alterations in chromatin state. The link between chromatin and aging has mostly focused on histone deacetylation by the Sir2 family, but less is known about the role of other histone modifications in longevity. Histone methylation plays a crucial role during development and in maintaining stem cell pluripotency in mammals. Regulators of histone methylation have been associated with aging in worms and flies, but characterization of their role and mechanism of action has been limited. Here we identify the ASH-2 trithorax complex, which trimethylates histone H3 at lysine 4 (H3K4), as a regulator of lifespan in C. elegans in a directed RNAi screen in fertile worms. Deficiencies in members of the ASH-2 complex–ASH-2 itself, WDR-5, and the H3K4 methyltransferase SET-2 extend worm lifespan. Conversely, the H3K4 demethylase RBR-2 is required for normal lifespan, consistent with the idea that an excess of H3K4 trimethylation–a mark associated with active chromatin–is detrimental for longevity. Lifespan extension induced by ASH-2 complex deficiency requires the presence of an intact adult germline and the continuous production of mature eggs. ASH-2 and RBR-2 act in the germline, at least in part, to regulate lifespan and to control a set of genes involved in lifespan determination. These results suggest that the longevity of the soma is regulated by an H3K4 methyltransferase/demethylase complex acting in the C. elegans germline.
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