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

项目摘要 我们祖先的经历对我们自己的健康有重要影响。人类研究 动物模型表明，一代人经历的压力或创伤会影响认知， 行为和生理的后续后代多代。然而， 跨代遗传已被证明是具有挑战性的研究，部分原因是缺乏表观遗传 可以追溯到多代人的表型。因此，我们开发了一种独特的模型， 秀丽隐杆线虫的跨代表观遗传，使我们能够将 在几十代中具有表型效应的分子变化。我们的长期目标是 这个模型可以理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被包裹在组蛋白的核心周围 proteins.组蛋白的修饰被添加和移除，调节DNA的进入，从而调节基因的表达。 表情组蛋白3（H3 K9 me 2）赖氨酸9位上添加两个甲基与基因 抑制，而添加到赖氨酸4相同的组蛋白（H3 K4 me）与基因激活。我们 发现属于H3 K4甲基化复合物的WDR-5突变，或者属于H3 K4甲基化复合物的WDR-5突变， JHDM-1是H3 K9 me 2的一种假定的去甲基化酶，它导致抑制性的H3 K9 me 2蛋白在全基因组范围内逐渐积累。 H3K9me2.这种积累导致两种突变体的寿命逐渐延长：wdr-5突变体获得 20代后寿命延长，而jhdm-1突变体在8代后获得寿命。我们将使用 这种跨代表观遗传的模型，以探索由遗传引起的后果， 抑制性H3 K9 me 2的不适当遗传。 我们假设抑制性H3 K9 me 2的世代变化影响基因表达， 影响健康和延长寿命的有机体生理学。该提案结合了无偏基因组 分析与经典的遗传方法在两个特定的目的：1。确定哪些特定途径响应于 通过检查健康状况、基因表达和 染色质可及性;和2.确定H3 K9 me 2积累如何与已知的 使用上位性分析的脂质代谢的寿命延长途径。我们的方法提供了两个主要的 优势：作为自花授粉的雌雄同体，C.秀丽线虫的基因是相同的， 使我们能够区分表观遗传特征和遗传特征;重要的是，C.秀丽线虫可以存活 对表观遗传的干扰，导致其他动物的胚胎死亡。的机制 表观遗传调控在所有真核生物中高度保守，包括线虫和哺乳动物。 因此，我们提出的研究将提供基本的见解，如何遗传的染色质 景观影响人类健康和疾病的基因表达。

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.