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: 10383952
• 负责人: Onur Birol
• 金额: $ 0.25万
• 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/10383952
• 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.

项目总结/摘要 细胞命运由差异基因表达指定，差异基因表达受染色质修饰调节， 获取DNA的权限配子是高度分化的细胞，具有独特的景观。他们 需要受精后的表观遗传重编程事件来消除配子的命运， 发展。这一过程的失调导致发育问题和潜在的人类疾病。在 1972 Beguet观察到亲本年龄影响野生型蠕虫下一代的生育力（C。 elegans）。年长的雌雄同体的后代与他们的兄弟姐妹相比， 年轻的父母为了确定年龄对后代生育力的影响是否是由于母体的缺陷， 在表观遗传重编程中，我在spr-5突变蠕虫中进行了类似的实验。SPR-5（LSD 1/KDM 1A） 是一种组蛋白去甲基化酶，可主动去除组蛋白3赖氨酸4（H3 K4 me 2）上的甲基化， 转录基因我们的实验室先前已经证明spr-5突变体C.优雅的人有一个跨代的 不育表型，由于增加H3 K4 me 2。值得注意的是，我发现spr-5突变蠕虫的后代 与野生型相比，高龄产妇（AMA）的生育力进一步受损。另外，我发现 来自早期母体年龄（EMA）Spring-5突变蠕虫的后代也具有降低的生育力。我的结果， 再加上Beguet的原始发现，表明父亲年龄对生育力下降的影响， 后代可能通过受损的H3 K4 me 2在受精时重编程。我提议调查此事 在我的新的C。elegans模型通过以下目的：目的1）确定为什么spr-5突变体 品系具有来自EMA和AMA雌雄同体的后代的生育力的恶化下降，目的2） 确定这种下降是否是由于跨代增加的H3 K4 me 2，以及目的3）调查 母亲年龄是否影响使用ChIP-seq的H3 K4 me 2重编程。了解潜在联系 母亲年龄和母亲表观遗传重编程之间的关系是重要的，因为a）年龄的影响， 我观察到的生育能力让人想起母亲年龄对自闭症发病率的影响，B）事实上， SPR-5同源物LSD 1的突变体，表现出自闭症样行为，和c）具有LSD 1突变的患者 表现出类似自闭症的症状因此，这些实验预计将为潜在的 翻译应用在未来。