Linking transgenerational epigenetic inheritance to gene expression and lifespan in C. elegans

将跨代表观遗传与线虫的基因表达和寿命联系起来

基本信息

批准号：
10358927
负责人：
Teresa Wei-sy Lee
金额：
$ 37.43万
依托单位：
UNIVERSITY OF MASSACHUSETTS LOWELL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10358927
关键词：
ATAC-seq Address Affect Animal Model Animals Behavior Biological Assay Caenorhabditis elegans Cells Child Chromatin Cognition Cognitive Complex Cytology DNA Defect Development Disease Embryo Environment Enzymes Epigenetic Process Eukaryota Evolution Experimental Models Famines Female Funding Future Generations Gene Activation Gene Expression Generations Genes Genetic Genetic Epistasis Genetic Transcription Genome Genomic approach Genomics Goals Health Hermaphroditism Histones Human Inherited Light Link Lipids Longevity Longevity Pathway Lysine Mammals Modeling Modification Molecular Muscle function Mutation Nematoda Non-Insulin-Dependent Diabetes Mellitus Pathway interactions Phenotype Physiological Physiology Population Proteins RNA Interference Regulation Regulatory Pathway Research Research Personnel Shapes Stress Survivors Testing Time Tissues Trauma Work aged biological adaptation to stress chromatin modification epigenetic regulation experience experimental study gene repression genetic approach genome-wide high risk histone methylation human model innovation insight lipid metabolism mRNA sequencing methyl group mutant obesity risk phenotypic data trait transgenerational epigenetic inheritance undergraduate student

项目摘要

PROJECT SUMMARY The experience of our ancestors has important consequences for our own health. Studies in humans and animal models have shown that stress or trauma experienced in one generation can affect the cognition, behavior, and physiology of subsequent descendants for multiple generations. However, the mechanisms of transgenerational inheritance have proven challenging to study, partially due to the scarcity of epigenetic phenotypes that can be traced through multiple generations. Thus, we have developed a unique model for transgenerational epigenetic inheritance in the nematode Caenorhabditis elegans that allows us to link molecular changes with phenotypic effects over dozens of generations. Our long-term goal is to leverage this model to understand how chromatin landscapes shape gene expression, cell fate, and physiology. In our cells, genomes are packaged into chromatin, in which DNA is wrapped around cores of histone proteins. Modifications are added and removed from histones, regulating access to DNA and therefore, gene expression. The addition of two methyl groups to lysine 9 of histone 3 (H3K9me2) is associated with gene repression, while addition to lysine 4 of the same histone (H3K4me) is associated with gene activation. We discovered that a mutation in either WDR-5, which belongs to an H3K4 methylating complex, or a mutation in JHDM-1, a putative demethylase for H3K9me2, causes the gradual, genome-wide accumulation of repressive H3K9me2. This accumulation causes a gradual lifespan extension in both mutants: wdr-5 mutants acquire longevity after twenty generations, while jhdm-1 mutants acquire longevity after eight generations. We will use this model of transgenerational epigenetic inheritance to probe the consequences caused by the inappropriate inheritance of repressive H3K9me2. We hypothesize that generational changes in repressive H3K9me2 affect gene expression and organismal physiology to impact health and extend lifespan. This proposal combines unbiased genomic analyses with classical genetic approaches in two Specific Aims: 1. Identify which specific pathways respond to the transgenerational accumulation of repressive H3K9me2 by examining health, gene expression, and chromatin accessibility; and 2. Determine how H3K9me2 accumulation genetically interacts with the known lifespan-extending pathway of lipid metabolism using epistasis analysis. Our approach offers two main advantages: as self-fertilizing hermaphrodites, homozygous populations of C. elegans are genetically identical, allowing us to distinguish epigenetic traits from genetic ones; and importantly, C. elegans can survive perturbations to epigenetic inheritance that cause embryonic lethality in other animals. The mechanisms of epigenetic regulation are highly conserved among all eukaryotes, including nematodes and mammals. Therefore, our proposed research will provide fundamental insight into how the inheritance of chromatin landscapes affects gene expression in human health and disease.

项目摘要我们祖先的经验对我们自己的健康有重要影响。人类的研究动物模型表明，一代人经历的压力或创伤会影响认知，多代后代的行为和生理学。但是，机制跨代遗产被证明是挑战性研究的，部分原因是表观遗传学的稀缺性可以追溯到多代的表型。因此，我们为线虫Caenorhabditis秀丽隐杆线虫中的跨代表观遗传遗传，使我们能够连接分子变化，几十一代的表型效应。我们的长期目标是利用该模型了解染色质景观如何塑造基因表达，细胞命运和生理学。在我们的细胞中，基因组被包装成染色质，其中DNA包裹在组蛋白的核心周围蛋白质。从组蛋白中添加并去除修饰，并调节对DNA的访问，因此，基因表达。在组蛋白3（H3K9me2）的赖氨酸9中添加两个甲基与基因有关抑制虽然在同一组蛋白（H3K4ME）中加上赖氨酸4的抑制作用与基因激活有关。我们发现WDR-5中的突变属于H3K4甲基化复合物或突变 JHDM-1是一种用于H3K9ME2的推定脱甲基酶 H3K9me2。这种积累会导致两个突变体的逐渐寿命延长：WDR-5突变体获取二十一代后的寿命，而JHDM-1突变体在八代后获得寿命。我们将使用这种转世表观遗传遗传模型，以探测由抑制性H3K9me2的不当继承。我们假设抑制性H3K9me2的世代变化会影响基因表达和有机生理，以影响健康并延长寿命。该建议结合了公正的基因组用经典遗传方法进行两个特定目的的分析：1。确定哪些特定途径对通过检查健康，基因表达和染色质可及性；和2。确定H3K9ME2如何与已知的遗传相互作用使用上科学分析，脂质代谢的寿命延伸途径。我们的方法提供了两个主要优势：作为雌雄同体的自我育种，秀丽隐杆线虫的纯合种群在遗传上相同，允许我们将表观遗传特征与遗传性状区分开；重要的是，秀丽隐杆线虫可以生存对表观遗传遗传的扰动引起其他动物的胚胎致死性。机制在包括线虫和哺乳动物在内的所有真核生物中，表观遗传调节都是高度保守的。因此，我们提出的研究将提供有关染色质遗传的基本见解景观影响人类健康和疾病中的基因表达。