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

基本信息

批准号：
10614794
负责人：
SUNDEEP KALANTRY
金额：
$ 8.21万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/10614794
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

项目摘要

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.

抽象的该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节和干细胞通过对多肉液组的研究。 Polycomb组包括一个突出的集合组蛋白修饰符对于执行各种发展过程至关重要，包括X- 染色体灭活，胚胎干细胞的自我更新和分化，细胞和组织规范，和哺乳动物的身体图案。 PolyComb抑制复合物2（PRC2）催化组蛋白H3K27Me3 通过甲基转移酶EZH2及其旁系同源物EZH1。 H3K27ME3充当关键的表观遗传标记发育，在人类疾病中失调。通过果蝇的大量工作，PRC2催化 H3K27me3已显示出表观遗传维持转录沉默。通过初步在早期小鼠胚胎中进行研究，我们建议PRC2也可能引发转录沉默。在 AIM 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复合物来发挥作用，以执行表观遗传沉默早期胚胎和胚胎衍生的干细胞中。在AIM 2中，我们将定义EED的非PRC角色植入前小鼠胚胎及其衍生的干细胞中的表观遗传沉默。最后，反击 H3K27me3仅由PRC2沉积的盛行教条，我们的结果表明了一个额外的 H3K27ME3催化剂。在AIM 3中，我们建议识别和剖析新型H3K27me3催化剂的功能外胚和胚胎干细胞。这三个目标都利用公正的方法来定义小说小鼠胚胎发生过程中PRC2蛋白和H3K27ME3催化的功能和机制早期胚胎衍生的干细胞。我们的中心假设是表观遗传调节的模式归因于可以通过替代机制和蛋白质发生多肉管组。预期的发现将增加我们的了解表观遗传逻辑的潜在胚胎发育以及表观遗传失调有助于人类疾病。