Environmental Modulation of Epigenetic Reprogramming in Pluripotent Cells

多能细胞表观遗传重编程的环境调节

• 批准号: 8390311
• 负责人: Miguel Ramalho-Santos
• 金额: $ 38.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8390311
• 关键词: Adult; Affect; Antioxidants; Ascorbic Acid; Ascorbic Acid Deficiency; Biological Assay; Cells; Coenzymes; Cytosine; DNA; DNA Methylation; Data; Development; Diet; Disease; Embryo; Embryonic Development; Environmental Pollution; Environmental Risk Factor; Enzymes; Epigenetic Process; Event; Exposure to; Failure; Fertility; Fetal Development; Fetus; Gene Expression; Generations; Genes; Goals; Gulo; Heavy Metals; Human; Immunoprecipitation; In Vitro; Incidence; Intake; Knowledge; L-gulonolactone oxidase; Laboratories; Lead; Light; Link; Malignant Neoplasms; Measures; Mediating; Memory; Methylation; Mission; Molecular; Mus; Mutant Strains Mice; Nutrient; Onset of illness; Outcome; Pathway interactions; Physiological Processes; Pluripotent Stem Cells; Predisposition; Pregnancy; Pregnancy Outcome; Process; Reaction; Regulation; Reproductive Biology; Research; Research Personnel; Resources; Role; Safety; Staging; Stem cells; Testing; Tetanus Helper Peptide; Toxic Environmental Substances; Toxicology; Toxin; United States National Institutes of Health; Work; X Chromosome; X Inactivation; base; developmental disease; drinking water; fetal; fetal medicine; human embryonic stem cell; imprint; improved; in vivo; induced pluripotent stem cell; innovation; insight; mouse model; novel; nutrition; pluripotency; preimplantation; promoter; response; self-renewal

DESCRIPTION (provided by applicant): Epigenetic reprogramming, and specifically the resetting of DNA methylation, is a key event during preimplantation development and in the fetal germline. Changes in the maternal diet or exposure to environmental contaminants can disrupt fetal epigenetic reprogramming and lead to pregnancy failure, developmental disorders or adult-onset disease, but the underlying molecular mechanisms remain unknown. It is important to fill this gap in order to develop informed safety standards for maternal diet and exposure to environmental toxins, and understand the epigenetic basis of adult-onset disease. The long-term goal of the investigators' research is to understand the epigenetic regulation of embryonic development. The objective of this application is to define the role of Vitamin C in epigenetic reprogramming in the embryo. Humans rely entirely on their diet for Vitamin C, which is essential for several physiological processes. Recent findings from our lab indicate that Vitamin C has a novel role in the direct regulation of epigenetic reprogramming, and specifically in DNA de-methylation and activation of germline genes in pluripotent stem cells. This proposal will test the innovative hypothesis that Vitamin C is a critical environmental regulator of epigenetic reprogramming in pluripotent stem cells and the fetal germline. The specific aims are: 1) to determine the mechanism of action of Vitamin C in epigenetic reprogramming. The investigators will test the role of Vitamin C as a potential co-factor of Tet enzymes in the generation of 5-hydroxymethyl-Cytosine at the promoters of germline genes; 2) to determine the functional consequences of exposure to Vitamin C in pluripotent stem cells. The role of Vitamin C will be assessed in the regulation of functions specific to pluripotent stem cells in vitro; and 3) to defie the Windows of Susceptibility (WOS) of Vitamin C-mediated epigenetic reprogramming. The investigators will use a validated mouse model of Vitamin C deficiency to determine the WOS to Vitamin C during the stages when epigenetic reprogramming occurs in vivo. This research is expected to provide fundamental new insights into the dietary and environmental modulation of epigenetic reprogramming during gestation, with significant impact in toxicology, maternal-fetal medicine, reproductive biology and cancer. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to the mission of the NIH because it aims to understand how nutrition and exposure to environmental factors affect stem cells in the fetus during pregnancy. This knowledge will inform better safety standards regarding diet and exposure to toxins during gestation, and may lead to improved pregnancy outcomes and reduced incidence of developmental and adult-onset disorders.

描述（由申请人提供）：表观遗传重编程，特别是 DNA 甲基化的重置，是植入前发育期间和胎儿种系中的关键事件。母亲饮食的变化或接触环境污染物可能会扰乱胎儿表观遗传重编程，并导致妊娠失败、发育障碍或成人发病的疾病，但潜在的分子机制仍不清楚。重要的是要填补这一空白，以便制定有关孕产妇饮食和环境毒素暴露的知情安全标准，并了解成人发病疾病的表观遗传基础。研究人员研究的长期目标是了解胚胎发育的表观遗传调控。该应用的目的是确定维生素 C 在胚胎表观遗传重编程中的作用。人类完全依赖饮食获取维生素 C，维生素 C 对于多种生理过程至关重要。我们实验室的最新研究结果表明，维生素 C 在表观遗传重编程的直接调节中具有新颖的作用，特别是在多能干细胞中 DNA 去甲基化和生殖系基因的激活中。该提案将检验一个创新假设，即维生素 C 是多能干细胞和胎儿种系表观遗传重编程的关键环境调节剂。具体目标是：1）确定维生素C在表观遗传重编程中的作用机制。研究人员将测试维生素 C 作为 Tet 酶的潜在辅助因子在种系基因启动子处生成 5-羟甲基-胞嘧啶的过程中的作用； 2) 确定多能干细胞暴露于维生素C的功能后果。将评估维生素 C 在体外调节多能干细胞特异功能中的作用； 3) 对抗维生素 C 介导的表观遗传重编程的易感性窗口 (WOS)。研究人员将使用经过验证的维生素 C 缺乏小鼠模型来确定体内表观遗传重编程发生阶段维生素 C 的 WOS。这项研究预计将为妊娠期间表观遗传重编程的饮食和环境调节提供基本的新见解，对毒理学、母胎医学、生殖生物学和癌症产生重大影响。 公共健康相关性：拟议的研究与 NIH 的使命相关，因为它旨在了解营养和环境因素暴露如何影响怀孕期间胎儿的干细胞。这些知识将为妊娠期间饮食和毒素接触提供更好的安全标准，并可能改善妊娠结局并减少发育障碍和成人发病率。