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Identifying the molecular mechanisms of transgenerational epigenetic inheritance

鉴定跨代表观遗传的分子机制

基本信息

批准号：
9069262
负责人：
Eric Lieberman Greer
金额：
$ 24.9万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9069262
关键词：
Address Affect Affinity Age American Society of Hematology Animal Model Antibodies Binding Binding Proteins Biochemistry Biological Caenorhabditis elegans Chemicals Chromatin Complex DNA Sequence Alteration Data Diet Habits Disease Enhancers Environmental Risk Factor Enzymes Epidemiology Epigenetic Process Euchromatin Fertility Funding Gene Activation Generations Genes Genetic Genetic Screening Genome Goals Health Heterochromatin Histone H3 Histones Homologous Gene Human Immunoprecipitation Inherited Laboratory Research Longevity Lysine Mediating Memory Mentorship Methylation Methyltransferase Modification Molecular Mutation Nematoda Parents Pathway interactions Phase Phenotype Proteins RNA Interference Research Sterility Testing Ursidae Family Work Yang base chromatin immunoprecipitation chromatin modification chromatin protein demethylation epigenetic memory gene repression genome-wide grandchild histone demethylase histone methyltransferase histone modification mutant obesity in children prevent reproductive research study transgenerational epigenetic inheritance transmission process

项目摘要

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.

描述（由申请人提供）：寿命受遗传和环境因素调节。我最近的工作表明，蠕虫的寿命也可以通过表观遗传方式进行调节。亲本中染色质调节复合物的突变对野生型后代的寿命具有跨代表观遗传效应。然而，目前尚不清楚表观遗传信息如何从一代遗传到下一代，以及这些信息如何调节有机体的寿命。我在这项提案中的目标是开始从机械上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，组蛋白去甲基化酶 SPR-5 的突变提供了长寿跨代表观遗传的第二个例子。具有该基因突变的蠕虫最初表型正常，然而，最终经过许多繁殖周期后，它们缺乏去甲基化酶的后代的寿命逐渐延长。通过基因 RNAi 筛选，我发现 H3K9 甲基结合蛋白介导 H3K4 去甲基化的渐进表观遗传记忆，导致生育能力日益降低和寿命延长。拟议的研究将有助于阐明 H3K9 甲基结合蛋白如何介导 H3K4 去甲基酶的作用，并研究改变组蛋白修饰如何延长寿命。这里提出的工作将在博士后阶段在染色质研究领域的世界领先者石杨博士的指导下进行，石杨博士发现了SPR-5的哺乳动物同源物LSD1，这是第一个组蛋白去甲基化酶。这笔研究资金将帮助建立一个独立的研究实验室，研究表观遗传信息如何调节寿命。