Epigenetic Control of Endothelial Gene Expression and Vascular Development

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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.**