Research Supplement to promote diversity for parent grant: Linking transgenerational epigenetic inheritance to gene expression and lifespan in C. elegans

项目总结 我们祖先的经历对我们自己的健康有重要的影响。对人类的研究 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。然而，它的作用机制 跨代遗传研究已被证明具有挑战性，部分原因是表观遗传学的稀缺。 可追溯到多代的表型。因此，我们开发了一种独特的模型 线虫秀丽线虫的跨代表观遗传遗传使我们能够将 经过几十代的分子变化和表型效应。我们的长期目标是利用 这一模型旨在了解染色质景观如何塑造基因表达、细胞命运和生理。 在我们的细胞中，基因组被包装成染色质，在染色质中，DNA包裹在组蛋白的核心上 蛋白质。组蛋白中的修饰被添加和移除，从而调节对DNA的访问，从而调节基因 表情。组蛋白3(H3K9me2)赖氨酸9上增加两个甲基与基因有关 抑制，而加入相同组蛋白的赖氨酸4(H3K4me)与基因激活有关。我们 发现WDR-5中的突变，属于H3K4甲基化复合体，或者是 JHDM-1，被认为是H3K9me2的去甲基酶，导致抑制性基因在全基因组范围内逐渐积累 H3K9me2。这种积累导致两个突变体的寿命逐渐延长：WDR-5突变体获得 20代后长寿，而jhdm-1突变体8代后长寿。我们将使用 这一跨代表观遗传模型探讨了 压抑性H3K9me2的不适当遗传。 我们假设抑制性H3K9me2基因的世代变化影响基因表达和 影响健康和延长寿命的生物生理学。这一建议结合了无偏见的基因组 用经典的遗传方法分析两个特定的目的：1.确定哪些特定的途径对 通过检查健康、基因表达和基因表达来研究抑制性H3K9me2的代际积累 染色质的可及性；以及2.确定H3K9me2的积累如何与已知的 用上位性分析研究脂类代谢的寿命延长途径。我们的方法提供两个主要方面 优势：作为自花授粉的两性人，线虫的纯合子种群在基因上是相同的， 使我们能够区分表观遗传特征和遗传特征；重要的是，线虫可以存活下来 对表观遗传造成其他动物胚胎致死的扰动。它的作用机制 表观遗传调控在所有真核生物中都是高度保守的，包括线虫和哺乳动物。 因此，我们提出的研究将为染色质的遗传提供基本的见解 景观会影响人类健康和疾病中的基因表达。

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.