Dynamic changes in RNA-chromatin interactome promote endothelial dysfunction

Abstract

Chromatins are pervasively attached by RNAs. Here, we asked whether global RNA-chromatin contacts are altered in a given cell type in a disease context, and whether these alterations impact gene expression and cell function. In endothelial cells (ECs) treated by high-glucose and TNF, we employed single-cell RNA-sequencing and in situ mapping of RNA-genome interaction (iMARGI) assay to delineate temporal changes in transcriptome and RNA-chromatin interactome. ECs displayed dramatic and heterogeneous changes in single cell transcriptome, accompanied by a dynamic and strong increase in inter-chromosomal RNA-DNA interactions, particularly among super enhancers (SEs). These SEs overlap with genes contributing to inflammatory response and endothelial mesenchymal transition (EndoMT), two key aspects of endothelial dysfunction. Perturbation of a high-glucose and TNF-activated interaction involving SEs overlapping LINC00607 and SERPINE1 attenuated the pro-inflammatory and pro-EndoMT gene induction and EC dysfunction. Our findings highlight RNA-chromatin contacts as a crucial regulatory feature in biological and disease processes, exemplified by endothelial dysfunction, a major mediator of numerous diseases.