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：
8581376
负责人：
Eric Lieberman Greer
金额：
$ 13.47万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8581376
关键词：
Address Affect Affinity Age American Society of Hematology Animal Model Antibodies Binding Binding Proteins Biochemistry Biological Caenorhabditis elegans Chemicals Chromatin Complex Data Diet Habits Disease Enhancers Environmental Risk Factor Enzymes Epidemiology Epigenetic Process Euchromatin Fertility Funding Gene Activation Gene Mutation 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 gene repression genome-wide grandchild histone methyltransferase histone modification mutant obesity in children prevent public health relevance reproductive research study 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的调节。我最近的工作表明，蠕虫中的寿命也可以以表观遗传方式调节。父母产生调节染色质复合物的突变对野生型后代的寿命具有跨代表观遗传作用。但是，目前尚不清楚如何从一代到第二代遗传信息以及该信息如何调节有机体寿命。我在此提案中的目标是开始从机械上定义如何将表观遗传信息从父母传播到后代，以调节线虫秀丽隐杆线虫中的寿命。初步结果表明，组蛋白脱甲基酶SPR-5的突变提供了转世表观遗传遗传的第二个例子。在该基因中具有突变的蠕虫最初是表型正常的，但是，在许多生殖周期之后，其后代缺乏脱甲基酶的寿命逐渐更长。通过遗传RNAi筛选，我发现H3K9甲基结合蛋白介导H3K4脱甲基化的进行性表观遗传记忆，从而导致越来越降低的肥料和更长的寿命。拟议的研究将有助于阐明H3K9甲基结合蛋白如何介导H3K4脱甲基酶的作用，并研究改变组蛋白的改变如何延长寿命。这里提出的工作将在博士后的指导下在博士后阶段进行，他是染色质研究的世界领导者，他发现SPR-5的哺乳动物同源物LSD1，LSD1，是第一个组蛋白脱甲基酶。这项研究资金将有助于推出一个独立的研究实验室，以研究表观遗传信息如何调节寿命。