Epigenetic Control of Endothelial Gene Expression and Vascular Development

内皮基因表达和血管发育的表观遗传控制

• 批准号: RGPIN-2016-05578
• 负责人: DelgadoOlguin, Paul
• 金额: $ 2.04万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709812
• 关键词: Epigenetic; Control; Endothelial; Gene; Expression

Embryonic development requires proper formation of the cardiovascular system. The long-term goal of my research program is to understand how formation of the cardiovascular system is regulated at the molecular level. To reach this goal, my lab studies how histone methyltransferases regulate the signaling and transcriptional programs that coordinate gene expression in developing cardiomyocytes and endothelial cells. By combining mouse phenotyping with genome-wide approaches, we have found that repressive histone methylation epigenetically coordinates the transcriptional programs controlling cardiovascular development. The proposed project focuses on the histone methyltransferase euchromatic histone-lysine N-methyltransferase (G9a). G9a positively and negatively regulates gene expression: 1. G9a represses expression by di-methylating lysine 9 of histone H3, and by scaffolding the interaction of repressor protein complexes at target genes. 2. G9a activates gene expression independently of histone methylation by interacting with transcription factors 3. G9a represses gene expression by methylating transcription factors. However, the transcriptional pathways, and/or the protein interactions by which G9a controls endothelial gene expression and vascular development are not known. My group recently found that G9a is required for proper establishment of the yolk sac vasculature pattern. We also discovered that G9a deficiency causes a significant decrease in the expression of the transcription factor Recombining Binding Protein Suppressor of Hairless (Rbpj). Rbpj is the major effector of Notch signaling, which is required for proper establishment of the yolk sac vasculature pattern. In this proposal we will: 1) Define the function of Rbpj as a regulator of vascular development downstream of G9a, 2) Identify the transcriptional pathways controlled by G9a in developing endothelium, and 3) Uncover protein interactions of G9a regulating endothelial gene expression. This work will provide significant insight into the epigenetic control of Notch signaling, which is an evolutionarily conserved pathway controlling vascular development. The proposed activities will find novel mechanisms controlling endothelial gene expression and development of the vascular system.

胚胎发育需要心血管系统的适当形成。我的研究计划的长期目标是了解心血管系统的形成是如何在分子水平上调节的。为了达到这一目标，我的实验室研究了组蛋白甲基转移酶如何调节信号和转录程序，这些程序协调发育中的心肌细胞和内皮细胞的基因表达。通过结合小鼠表型和全基因组方法，我们发现抑制性组蛋白甲基化在表观遗传上协调了控制心血管发育的转录程序。拟议的项目重点是组蛋白甲基转移酶、常染色质组蛋白赖氨酸N-甲基转移酶(G9a)。G9a对基因表达有正向和负向调节作用：1.G9a通过组蛋白H3赖氨酸9的二甲基化和抑制蛋白复合体与靶基因的相互作用来抑制基因的表达。2.G9a通过与转录因子相互作用独立于组蛋白甲基化激活基因表达3.G9a通过甲基化转录因子抑制基因表达。然而，G9a控制内皮基因表达和血管发育的转录途径和/或蛋白质相互作用尚不清楚。我的团队最近发现，G9a是正确建立卵黄囊血管模式所必需的。我们还发现，G9a缺乏导致转录因子重组结合蛋白抑制物无毛(Rbpj)表达显著降低。Rbpj是Notch信号的主要效应者，这是正确建立卵黄囊血管模式所必需的。在本提案中，我们将：1)将Rbpj定义为G9a下游血管发育的调节因子；2)确定G9a调控内皮细胞发育的转录途径；3)揭示G9a调控内皮基因表达的蛋白质相互作用。这项工作将对Notch信号的表观遗传控制提供重要的见解，Notch信号是一种进化上保守的控制血管发育的途径。所提出的活动将发现控制血管系统内皮细胞基因表达和发展的新机制。