Investigating Novel Modes of Epigenetic Regulation Through the Polycomb Group

通过多梳组研究表观遗传调控的新模式

• 批准号: 9922974
• 负责人: SUNDEEP KALANTRY
• 金额: $ 42.41万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-05 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922974
• 关键词: Ablation; Biochemical; Body Patterning; Catalysis; Cells; Chromatin; Complex; Defect; Deposition; Development; Developmental Process; Disease; Drosophila genus; EZH2 gene; Embryo; Embryonic Development; Endoderm; Enzymes; Epigenetic Process; Female; Future; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Transcription; Genome; Histone H3; Histones; Human; In Vitro; Investigation; Knowledge; Link; Logic; Lysine; Maintenance; Mammals; Meiosis; Memory; Methyltransferase; Mitosis; Mitotic; Mus; Oocytes; Organism; Phase; Polycomb; Proteins; Proteomics; Repression; Role; Stereotyping; Testing; Therapeutic; Tissues; Transcriptional Regulation; Work; X Inactivation; blastocyst; catalyst; chromatin modification; embryonic stem cell; epigenetic regulation; epigenome; genome-wide; human disease; imprint; knock-down; loss of function mutation; novel; paralogous gene; pluripotency; preimplantation; self-renewal; small hairpin RNA; stem cells; trophoblast

Abstract The objective of this proposal is to illuminate epigenetic transcriptional regulation during mouse embryogenesis and stem cells through investigations of the Polycomb group. The Polycomb group comprises a prominent set of histone modifiers that are essential for the execution of diverse developmental processes, including X- chromosome inactivation, self-renewal and differentiation of embryonic stem cells, cell and tissue specification, and body patterning in mammals. The Polycomb repressive complex 2 (PRC2) catalyzes histone H3K27me3 through the methyltransferases EZH2 and its paralog EZH1. H3K27me3 functions as a key epigenetic mark in development and is dysregulated in human diseases. Through much work in Drosophila, PRC2-catalyzed H3K27me3 has been shown to epigenetically maintain transcriptional silencing. Through preliminary investigations in early mouse embryos, we propose that PRC2 may also initiate transcriptional silencing. In Aim 1, we will therefore test the role of PRC2 in initiating epigenetic transcriptional silencing. We have further found the PRC2 protein EED can function independently of PRC complexes to execute epigenetic silencing in early embryos and in embryo embryo-derived stem cells. In Aim 2, we will define the non-PRC role of EED in epigenetic silencing in preimplantation mouse embryos and its derived stem cells. Finally, countering the prevailing dogma that H3K27me3 is deposited solely by PRC2 our results demonstrate an additional H3K27me3 catalyst. In Aim 3, we propose to identify and dissect the function of a novel H3K27me3 catalyst in extra-embryonic and embryonic stem cells. All three Aims utilize unbiased approaches to define novel functions and mechanisms of PRC2 proteins and H3K27me3 catalysis during mouse embryogenesis and in early embryo-derived stem cells. Our central hypothesis is that the mode of epigenetic regulation ascribed to the Polycomb group can occur via alternate mechanisms and proteins. The expected findings will increase our understanding of the epigenetic logic underlying embryonic development and how epigenetic dysregulation contributes to human disease.

摘要 这项建议的目的是阐明小鼠胚胎发育过程中的表观遗传转录调控。 和干细胞通过对Polycomb组的研究。聚梳组包括一个突出的集合 组蛋白修饰物对于执行不同的发育过程是必不可少的，包括X- 胚胎干细胞的染色体失活、自我更新和分化，细胞和组织规格， 以及哺乳动物的身体图案。多梳抑制复合体2(PRC2)催化组蛋白H3K27me3 通过甲基转移酶EZH2及其类似物EZH1。H3K27me3是一个关键的表观遗传标记 并在人类疾病中处于失调状态。通过在果蝇中的大量研究，PrC2催化 H3K27me3已被证明在表观遗传学上维持转录沉默。通过初选 在对小鼠早期胚胎的研究中，我们认为PRC2也可能启动转录沉默。在……里面 目的1，我们将测试PrC2在启动表观遗传转录沉默中的作用。我们还有更多 发现PRC2蛋白EED可以独立于PRC复合体发挥作用，在 早期胚胎和胚胎来源的干细胞。在目标2中，我们将定义EED在中国以外的角色 植入前小鼠胚胎及其衍生干细胞中的表观遗传沉默。最后，应对 普遍认为H3K27me3是由PRC2单独沉积的我们的结果证明了另一个 H3K27Me3催化剂。在目标3中，我们建议鉴定和剖析一种新型H3K27me3催化剂在 胚胎外干细胞和胚胎干细胞。这三个目的都是使用不偏不倚的方法来定义小说 PRC2蛋白和H3K27me3催化在小鼠胚胎发育中的作用及其机制 早期胚胎来源的干细胞。我们的中心假设是表观遗传调控模式归因于 多梳基团可以通过其他机制和蛋白质发生。预期的结果将增加我们的 理解胚胎发育的表观遗传逻辑以及如何表观遗传失调 会导致人类疾病。