Abstract 251: Regulation Of Endotheliopathy By Chromatin-associated Long Non-coding RNA

Lining the critical interface between circulating blood and vascular wall, endothelial cells (ECs) play vital functions in health and disease. The optimal gene expression in ECs is essential to maintain endothelial homeostasis, and its dysregulation can lead to EC dysfunction or endotheliopathy, a common mechanism underlying many metabolic and cardiovascular diseases. Through chromatin-RNA contact profiling, we have identified several chromatin-associated long non-coding RNA (lncRNAs) that play essential roles in the regulation of endothelial function, including endothelial nitric oxide production, angiogenesis, endothelial-mesenchymal transition, and inflammatory activation. These include nuclear genome-transcribed lncRNAs, e.g. lncRNA-enhancing endothelial nitric oxide synthase (LEENE) and LINC00607 that promotes expression of fibronectin and plasminogen activator inhibitor-1. Our recent study has also revealed that mitochondria transcribed RNAs (mtRNA) are pervasively attached to nuclear chromatin and such mtRNA-association with chromatin is increased by pro-inflammatory, diabetes-mimicking stimuli. Suppression of a mitochondrial lncRNA in ECs attenuates nascent RNA transcription from the nuclear genome, including that of critical genes promoting pro-inflammatory activation. Finally, we show increased nuclear localization of multiple mtRNAs in the ECs of human diabetic donors. Together, these data highlight an emerging role of chromatin-associated lncRNAs in regulating endothelial biology.