The effect of age on epigenetic reprogramming in C.elegans

年龄对线虫表观遗传重编程的影响

• 批准号: 10153831
• 负责人: Onur Birol
• 金额: $ 6.86万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153831
• 关键词: Affect; Age; Animals; Behavior; Biological Models; Caenorhabditis elegans; Cell Differentiation process; ChIP-seq; Child; Coupled; DNA; Data; Defect; Development; Elderly; Embryo; Enzymes; Epigenetic Process; Event; Exhibits; Fertility; Fertilization; Foundations; Future; Generations; Genes; Germ Cells; Hermaphroditism; Histones; Homologous Gene; Incidence; Inherited; Investigation; KDM1A gene; Knowledge; Link; Lysine; Maternal Age; Meiosis; Methylation; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Oocytes; Paper; Parental Ages; Parents; Paternal Age; Patients; Pattern; Personal Satisfaction; Phenotype; Play; Pregnancy; Process; Production; Publishing; Reporting; Role; Siblings; Specific qualifier value; Sperm Count Procedure; Sterility; Symptoms; Tissue-Specific Gene Expression; Totipotent; Wild Type Mouse; advanced maternal age; age effect; age related; autism spectrum disorder; autistic; c new; chromatin modification; experimental study; fitness; follow-up; histone demethylase; human data; human disease; mortality; mutant; offspring; sperm cell; zygote

PROJECT SUMMARY/ABSTRACT Cellular fate is specified by differential gene expression, which is regulated by chromatin modifications allowing for controlled access to DNA. Gametes are highly differentiated cells, harboring distinctive landscapes. They require an epigenetic reprogramming event after fertilization to erase gamete fate and allow a totipotent zygote to develop. Dysregulation of this process leads to developmental problems and potentially human disease. In 1972 Beguet observed that parental age affects fertility of the following generation in wild type worms (C. elegans). Offspring from the older hermaphrodites had a smaller brood size compared to their siblings from younger parents. To determine if this effect of age on the fertility of progeny is due to defects in maternal epigenetic reprogramming, I performed analogous experiments in spr-5 mutant worms. SPR-5 (LSD1/KDM1A) is a histone demethylase that removes the methylation on histone 3 lysine 4 (H3K4me2) from actively transcribed genes. Our lab has previously shown that spr-5 mutant C. elegans have a transgenerational sterility phenotype, due to increasing H3K4me2. Remarkably, I found that progeny of spr-5 mutant worms have a further compromised fertility with advanced maternal age (AMA) compared to wild type. In addition, I found that progeny of spr-5 mutant worms from early maternal age (EMA) also have reduced fertility. My results, coupled with Beguet’s original findings, suggest that the effect of paternal age on reduced fecundity in the offspring may be through compromised H3K4me2 reprogramming at fertilization. I propose to investigate this possibility in my new C. elegans model through the following aims: Aim 1) determining why the spr-5 mutant line has an exacerbated decline in the fertility of progeny from EMA and AMA hermaphrodites, Aim 2) determining whether this decline is due to trans-generationally increased H3K4me2, and Aim 3) investigating whether maternal age affects H3K4me2 reprogramming using ChIP-seq. Understanding the potential link between maternal age and maternal epigenetic reprogramming is important because a) the effect of age of fecundity that I observe is reminiscent of the maternal age effect on the rate of autism, b) the fact that mice mutant for the SPR-5 homolog, LSD1, manifest autism-like behavior, and c) patients with LSD1 mutations display autistic-like symptoms. Thus, these experiments are anticipated to provide a foundation for potential translational applications in the future.

项目摘要/摘要 细胞命运由差异基因表达决定，而差异基因表达由染色质修饰调节，从而允许 有控制地获取DNA。配子是高度分化的细胞，具有独特的景观。他们 需要在受精后发生表观遗传重编程事件以消除配子命运并允许全能受精卵 去发展。这一过程的失调会导致发育问题，并可能导致人类疾病。在……里面 1972年，贝盖观察到，在野生型蠕虫(C. 优雅女装)。年龄较大的两性人的后代比他们的兄弟姐妹有更小的后代大小 更年轻的父母。为了确定这种年龄对后代生育能力的影响是否源于母体的缺陷 表观遗传重新编程，我在spr-5突变蠕虫身上做了类似的实验。SPR-5(LSD1/KDM1A) 是一种组蛋白去甲基酶，它能去除组蛋白3赖氨酸4(H3K4me2)上的甲基化。 转录的基因。我们的实验室先前已经证明，spr-5突变的线虫具有跨代 不育表型，由于H3K4me2增加。值得注意的是，我发现spr-5突变蠕虫的后代 与野生型相比，母体年龄(AMA)更高，生育力进一步下降。另外，我发现 来自早期母体年龄(EMA)的spr-5突变虫子代也降低了生育力。我的结果是， 再加上贝盖最初的发现，表明父亲的年龄对婴儿生育力下降的影响 后代可能通过受精时受损的H3K4me2重新编程。我提议对此进行调查 通过以下目标在我的新线虫模型中实现可能性：目标1)确定为什么spr-5突变体 LINE的EMA和AMA两性后代的可育性下降加剧，目标2) 确定这种下降是否是由于跨代增加的H3K4me2，并目的3)调查 孕妇年龄是否影响使用CHIP-SEQ的H3K4me2重编程。了解潜在的链接 母体年龄和母体表观遗传重编程之间很重要，因为a)年龄的影响 我观察到的繁殖力让人想起母亲年龄对自闭症发病率的影响，b)小鼠 SPR-5同源基因突变，LSD1，表现出自闭症样行为，以及c)LSD1突变患者 表现出类似自闭症的症状。因此，这些实验有望为潜在的 未来的翻译应用。