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: 9090198
• 负责人: Miguel Ramalho-Santos
• 金额: $ 38.75万
• 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/9090198
• 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; Health; Heavy Metals; Human; Immunoprecipitation; In Vitro; Incidence; Intake; Knowledge; L-gulonolactone oxidase; Laboratories; Lead; Light; Link; Malignant Neoplasms; Measures; Mediating; 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; epigenetic memory; epigenetic regulation; 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.

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，是植入前发育和胎儿生殖系中的关键事件。母体饮食的变化或暴露于环境污染物可能会破坏胎儿的表观遗传重编程，并导致妊娠失败，发育障碍或成人发病疾病，但潜在的分子机制仍然未知。必须填补这一空白，以便为产妇饮食和接触环境毒素制定知情的安全标准，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。本申请的目的是确定维生素C在胚胎表观遗传重编程中的作用。人类完全依赖于他们的饮食维生素C，这是必不可少的几个生理过程。我们实验室的最新发现表明，维生素C在表观遗传重编程的直接调节中具有新的作用，特别是在多能干细胞中的DNA去甲基化和生殖系基因的激活中。这项提案将测试创新的假设，即维生素C是多能干细胞和胎儿生殖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作为泰特酶的潜在辅因子在生殖系基因启动子处产生5-羟甲基胞嘧啶中的作用; 2）确定多能干细胞中暴露于维生素C的功能后果。将评估维生素C在体外对多能干细胞特异性功能的调节中的作用;以及3）确定维生素C介导的表观遗传重编程的易感性窗口（WOS）。研究人员将使用经验证的维生素C缺乏症小鼠模型来确定在体内发生表观遗传重编程的阶段期间维生素C的WOS。这项研究有望为妊娠期间表观遗传重编程的饮食和环境调节提供新的基本见解，并对毒理学，母胎医学，生殖生物学和癌症产生重大影响。

项目成果

Global Hypertranscription in the Mouse Embryonic Germline.

• DOI: 10.1016/j.celrep.2017.05.036
• 发表时间: 2017-06-06
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Percharde M;Wong P;Ramalho-Santos M
• 通讯作者: Ramalho-Santos M

YAP Induces Human Naive Pluripotency.

• DOI: 10.1016/j.celrep.2016.02.036
• 发表时间: 2016-03-15
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Qin H;Hejna M;Liu Y;Percharde M;Wossidlo M;Blouin L;Durruthy-Durruthy J;Wong P;Qi Z;Yu J;Qi LS;Sebastiano V;Song JS;Ramalho-Santos M
• 通讯作者: Ramalho-Santos M