Abstract 250: Endothelial functional Regulation by Enhancer-Associated Long Non-Coding RNAs
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY(2018)
摘要
Vascular endothelium constitutes the critical interface between circulating blood and vessel wall. Long non-coding RNAs (lncRNAs) are important regulators in gene expression and chromotin remodeling. We recently identified a l ncRNA that e nhances e ndothelial n itric oxide synthase (eNOS) e xpression (LEENE), that is encoded in a distal enhancer region and mediates long-range DNA interaction to promote the eNOS expression. We now extend from this prototype using a systematic approach to identify enhancer-associated lncRNAs and their molecular and functional regulation of endothelial gene expression. We integrate a variety of publicly available high-throughput sequencing datasets (including various chromatin immunoprecipitation-sequencing) that provide information on histone modifications and transcriptional activity and high-resolution chromatin conformation capture combined with sequencing (4C-seq) profiles generated in our own lab. From these analyses, we identified over 200 enhancer-associated lncRNA candidates with high potential to regulate endothelial gene expression. Quantitative PCR analysis verified that 7 out of the top 10 ranked candidates are differentially regulated by stimuli that alter endothelial gene expression and functions, including high-glucose, TNFα, atorvastatin, and metformin. Using CRISPR-cas9 gene editing to delete these lncRNA-associated enhancer regions and locked nucleic acid-mediated lncRNA inhibition, we demonstrated that the loss-of-function of these lncRNAs lead to significant alteration of endothelial gene expression, including those involved in angiogenesis and eNOS signaling. Collectively, these lncRNAs play an essential role in epigenetic regulation of endothelial functions; the identification of these lncRNAs can have significant impacts on understanding of endothelial homeostasis and dysfunction.
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