The scientific goal of this project is to gain further insjght into how chromatin-based pathways contribute to endothelial cell (EC) gene expression. A focus of our studies is the gene responsible for the production of NO by vascular endothelium, namely endothelial nitric oxide synthase (eNOS). We have reported that the promoter of the eNOS gene is hypomethylated in endothelial cells both in vitro and in vivo. In contrast, the promoter was densely methylated in genomic DNA isolated from cell types that do not express eNOS. We have also reported that the nucleosomes that encompass the eNOS core promoter were highly enriched in activating histone modifications in expressing versus non-expressing cell types. The overall hypothesis of this project is that epigenetic processes play a major role in the spatial and temporal regulation of EC gene expression. This project is extremely complementary to our overall PPG theme. We will collaborate with all members of this PPG and take full advantage of the PPG Cores.
In Aim I we will define whether the maintenance of cell-specific epigenetic marks at the eNOS proximal promoter is critically important for maintaining constitutive transcription of eNOS in ECs and transcriptional repression in differentiated cell types that do not express eNOS.
In Aim II we will define the contribution of epigenetic pathways to the temporal regulation of eNOS expression during EC differentiation and vascular development. We will use in vitro and in vivo approaches. We have found differential patterns of epigenetic modifications at the promoters of a number of EC-specific genes suggesting that our findings with the eNOS gene may be broadly relevant. Therefore, in Aim III we will use a ChlP-on-chip approach to define the contribution of epigenetic pathways to the global regulation of EC-specific gene expression. We will also identify large-intergenic non-coding RNAs that especially enriched in ECs. We anticipate that our studies will provide new insight into the contribution of epigenetic pathways to global patterns of EC-specific gene expression.

Public Health Relevance

Our PPG in general, and this project specifically, seek to understand how endothelial cell (EC) phenotypes are differentially regulated in space and time, in both health and disease. Our work here is relevant because we believe that an enhanced understanding of chromatin-based pathways of EC gene expression has important translational implications for regenerative medicine and blood vessel diseases. Our work could be transformative for future clinical approaches to reprogramming of differentiated cell types in vitro and reestablishing the normal pattern of gene expression in diseased blood vessels in situ. Our success in gaining an enhanced understanding of these newer paradigms offers the hope of changing clinical approaches to the diagnosis and treatment of human diseases that are characterized by perturbations in endothelial phenotype.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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Beth Israel Deaconess Medical Center
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Yuan, Lei; Chan, Gary C; Beeler, David et al. (2016) A role of stochastic phenotype switching in generating mosaic endothelial cell heterogeneity. Nat Commun 7:10160
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