Identifying the molecular mechanisms of transgenerational epigenetic inheritance

描述(申请人提供)：长寿受遗传和环境因素的影响。我最近的研究表明，蠕虫的寿命也可以通过表观遗传的方式进行调节。在亲代中，染色质调节复合体的突变对野生型后代的寿命有跨代表观遗传效应。然而，尚不清楚表观遗传信息是如何从一代遗传到下一代的，以及这种信息如何调节生物的寿命。我在这项提案中的目标是开始机械地定义表观遗传信息如何从父母传递给后代，以调节线虫的寿命。初步结果表明，组蛋白去甲基酶SPR-5的突变提供了第二个跨代表观遗传长寿的例子。带有该基因突变的蠕虫最初是表型正常的，然而，经过多次繁殖周期后，它们缺乏去甲基酶的后代的寿命逐渐延长。通过遗传RNAi筛选，我发现H3K9甲基结合蛋白介导了H3K4去甲基化的渐进性表观遗传记忆，导致生育力日益下降和寿命延长。这项拟议的研究将有助于阐明H3K9甲基结合蛋白如何介导H3K4去甲基酶的影响，并研究改变的组蛋白修饰如何延长寿命。本文提出的工作将在世界染色质研究领先者杨石博士的指导下进行，他发现了SPR-5的哺乳动物同源物LSD1，作为第一个组蛋白去甲基酶。这笔研究资金将帮助启动一个独立的研究实验室，研究表观遗传信息如何调节寿命。

DESCRIPTION (provided by applicant): Longevity is regulated by genetic as well as environmental factors. My recent work has shown that longevity in worms can also be regulated in an epigenetic manner. Mutations of a chromatin regulating complex in the parental generation have a transgenerational epigenetic effect on the longevity of wild-type descendants. However, it is unclear how epigenetic information is inherited from one generation to the next and how this information regulates organismal longevity. My goal in this proposal is to begin to define mechanistically how epigenetic information can be transmitted from parents to descendants to regulate longevity in the nematode C. elegans. Preliminary results suggest that mutation of the histone demethylase SPR-5 provides a second example of transgenerational epigenetic inheritance of longevity. Worms with a mutation in this gene are initially phenotypically normal, however, eventually after many reproductive cycles their descendants lacking the demethylase have progressively longer lifespans. Through a genetic RNAi screen I found that an H3K9 methyl binding protein mediates progressive epigenetic memory of H3K4 demethylation, leading to increasingly reduced fertillity and longer lifespan. The proposed research will help elucidate how an H3K9 methyl binding protein can mediate the effects of an H3K4 demethylase and examine how altered histone modifications can extend longevity. The work proposed here will be conducted in the postdoctoral phase under the mentorship of Dr. Yang Shi, a world leader in chromatin research, who discovered the mammalian homologue of SPR-5, LSD1, as the first histone demethylase. This research funding will help launch an independent research laboratory to study how epigenetic information regulates longevity.