Epigenetic Control of Endothelial Gene Expression and Vascular Development

胚胎发育需要心血管系统的适当形成。我的研究项目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受到调节的。为了达到这一目标，我的实验室研究组蛋白甲基转移酶如何调节发育中的心肌细胞和内皮细胞中协调基因表达的信号和转录程序。通过将小鼠表型分析与全基因组方法相结合，我们发现抑制性组蛋白甲基化在表观遗传学上协调了控制心血管发育的转录程序。拟建项目重点研究组蛋白甲基转移酶常染色组蛋白赖氨酸n -甲基转移酶（G9a）。G9a正、负调控基因表达：G9a通过组蛋白H3的赖氨酸9二甲基化和抑制蛋白复合物在靶基因上的脚手架相互作用来抑制表达。2. G9a通过与转录因子3相互作用，独立于组蛋白甲基化激活基因表达。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是卵黄囊血管模式正常建立所必需的。我们还发现G9a缺乏导致转录因子重组结合蛋白抑制因子（Rbpj）的表达显著降低。Rbpj是Notch信号的主要影响因子，它是卵黄囊血管模式正常建立所必需的。在本文中，我们将：1)确定Rbpj作为G9a下游血管发育的调节因子的功能；2)确定G9a在内皮发育中的转录调控途径；3)揭示G9a调节内皮基因表达的蛋白相互作用。这项工作将为Notch信号的表观遗传控制提供重要的见解，Notch信号是一个控制血管发育的进化保守途径。所提出的活动将发现控制血管系统内皮基因表达和发育的新机制

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.**