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: 10396014
• 负责人: SUNDEEP KALANTRY
• 金额: $ 41.56万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396014
• 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; epigenetic silencing; 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 stem cell

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 这个建议的目的是阐明小鼠胚胎发生过程中的表观遗传转录调控 和干细胞的研究。Polycomb集团由一群杰出的人组成 组蛋白修饰剂是执行各种发育过程所必需的，包括X- 染色体失活，胚胎干细胞的自我更新和分化，细胞和组织特化， 和哺乳动物的身体模式。Polycomb阻遏复合物2（PRC 2）催化组蛋白H3 K27 me 3 通过甲基转移酶EZH 2和其副酶EZH 1。H3 K27 me 3作为一个关键的表观遗传标记， 发展和失调的人类疾病。通过对果蝇的大量研究，PRC 2催化的 H3 K27 me 3已经显示出表观遗传地维持转录沉默。通过初步 在早期小鼠胚胎中的研究中，我们提出PRC 2也可以启动转录沉默。在 因此，我们将测试PRC 2在启动表观遗传转录沉默中的作用。我们进一步 发现PRC 2蛋白EED可以独立于PRC复合物发挥作用，在细胞中执行表观遗传沉默。 早期胚胎和胚胎来源的干细胞。在目标2中，我们将定义EED在以下方面的非中华人民共和国角色： 植入前小鼠胚胎及其衍生干细胞中的表观遗传沉默。最后，反击 H3 K27 me 3仅由PRC 2沉积的流行教条，我们的结果证明了另外的 H3 K27 me 3催化剂。在目标3中，我们提出鉴定和剖析新型H3 K27 me 3催化剂在催化裂化中的功能。 胚胎外和胚胎干细胞。所有三个目标都利用无偏见的方法来定义新的 PRC 2蛋白和H3 K27 me 3催化在小鼠胚胎发生和发育中的功能和机制 早期胚胎干细胞我们的中心假设是表观遗传调节模式归因于 Polycomb组可以通过替代机制和蛋白质发生。预期的结果将增加我们的 了解胚胎发育背后的表观遗传逻辑以及表观遗传失调如何 导致人类疾病。