Genomic Landscapes of Noncoding RNAs Regulating and Expression in Endothelial Cells.

Vascular endothelial growth factors (VEGFs) are best known as key regulators of angiogenesis and lymphangiogenesis. Although VEGFs have been promising therapeutic targets for various cardiovascular diseases, their regulatory landscape in endothelial cells remains elusive. Several studies have highlighted the involvement of noncoding RNAs (ncRNAs) in the modulation of expression. In this study, we investigated the role of two classes of ncRNAs, long ncRNAs (lncRNAs) and enhancer RNAs (eRNAs), in the transcriptional regulation of and . By integrating genome-wide global run-on sequencing (GRO-Seq) and chromosome conformation capture (Hi-C) data, we identified putative lncRNAs and eRNAs associated with and genes in endothelial cells. A subset of the identified putative enhancers demonstrated regulatory activity in a reporter assay. Importantly, we demonstrate that deletion of enhancers and lncRNAs by CRISPR/Cas9 promoted significant changes in and expression. Transcriptome sequencing (RNA-Seq) data from lncRNA deletions showed downstream factors implicated in and -linked pathways, such as angiogenesis and lymphangiogenesis, suggesting functional roles for these lncRNAs. Our study uncovers novel lncRNAs and eRNAs regulating and that can be targeted to modulate the expression of these important molecules in endothelial cells.