A novel epigenetic mechanism in early embryogenesis

早期胚胎发生中的一种新的表观遗传机制

• 批准号: 10584485
• 负责人: zhuo Andrew Xiao
• 金额: $ 46万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584485
• 关键词: Adult; Biology; Brain; Chromatin Structure; DNA; DNA Methylation; DNA Transposable Elements; Development; Embryonic Development; Epigenetic Process; Evolution; Human; Mammals; Mus; Outcome; Placenta; Play; Regulation; Research; Role; Series; Specific qualifier value; Stress; Structure; Tissues; chromatin remodeling; embryonic stem cell; human disease; neoplastic cell; novel; pluripotency; stem cell fate; stem cells; trophoblast; trophoblast stem cell; tumorigenesis

Mammalian early embryogenesis is a fundamental question in biology. Recent studies have demonstrated that global remodeling of chromatin structure plays a critical role in acquiring and maintaining toti- or pluri-potency. Although their exact function remains elusive, endogenous transposable elements (TEs), remnants of ancient transposons, are associated with dynamic chromatin remodeling in early embryogenesis. Furthermore, although trophoblast stem cells (TSCs) play essential roles in supporting embryonic development, little is known about their chromatin structure. TEs plays an essential role in the acquirement of placenta in eutherians during evolution. Intriguingly, the specification of the trophoblast lineage occurs when traditional epigenetic marks reaches the lowest point, indicative of the existence of novel mechanisms. DNA methylation is a critical factor in the regulation of chromatin structures. A series of recent studies, including ours, have discovered a novel type of DNA methylation, N6- methyladenine (N6-mA), in metazoans. In general, N6-mA is expressed at very low levels in adult mammalian tissues and can be upregulated under environmental stress or in tumorigenesis. N6-mA levels are greatly elevated in early embryogenesis in various metazoans, including mammals. Interestingly, we and others also demonstrated the specific role of N6-mA in silencing TEs in mouse embryonic stem cells, brains and human tumor cells. Our most recent results demonstrated a surprising function of N6-mA in promoting dynamic chromatin structures in stem cells thereby promoting the stem cell fate (TSCs), via stabilizing DNA secondary structure at TEs. This proposal aims to further investigate this novel mechanism. The outcome of this proposal will pave the way to a new research direction in epigenetics and embryogenesis.

哺乳动物早期胚胎发生是生物学中的一个基本问题。最近的研究 已经证明，染色质结构的整体重塑在获得 和维持全能性或多能性。虽然它们的确切功能仍然难以捉摸， 内源性转座因子（TEs）是古老转座子的残余， 在早期胚胎发生中动态染色质重塑。此外，虽然滋养层 干细胞（TSCs）在支持胚胎发育中发挥重要作用，但目前知之甚少 关于它们的染色质结构。TE在胎盘的获得中发挥着重要作用 进化过程中的真兽目动物。有趣的是，滋养层细胞谱系的特化发生在 传统的表观遗传标记达到最低点，表明小说的存在 机制等 DNA甲基化是调节染色质结构的关键因素。一系列 最近的研究，包括我们的研究，发现了一种新型的DNA甲基化，N6- 甲基腺嘌呤（N6-mA），在后生动物中。一般来说，N6-mA表示在非常低的水平， 并且可以在环境应激下或在哺乳动物中被上调。 肿瘤发生N6-mA水平在各种后生动物的早期胚胎发生中大大升高， 包括哺乳动物。有趣的是，我们和其他人还证明了N6-mA的特定作用， 在小鼠胚胎干细胞、大脑和人类肿瘤细胞中沉默TE。我们最 最近的结果表明，N6-mA在促进动态染色质中具有令人惊讶的功能， 干细胞中的结构，从而通过稳定DNA促进干细胞命运（TSCs） 二级结构在TE。该提案旨在进一步研究这种新机制。 该提案的结果将为表观遗传学的新研究方向铺平道路， 胚胎发生