Stress-induced RNA–chromatin interactions promote endothelial dysfunction

• Published in: Nature communications 2020-10, Vol.11 (1), p.5211-13, Article 5211
• Main Authors: Calandrelli, Riccardo, Xu, Lixia, Luo, Yingjun, Wu, Weixin, Fan, Xiaochen, Nguyen, Tri, Chen, Chien-Ju, Sriram, Kiran, Tang, Xiaofang, Burns, Andrew B., Natarajan, Rama, Chen, Zhen Bouman, Zhong, Sheng
• Format: Article
• Language: English
• Subjects: 13/109; 14/63; 38/1; 38/32; 38/39; 38/77; 38/88; 38/90; 38/91; 45/15; 631/337; 631/553/2711; 692/699; Chromatin - physiology; Diabetes Mellitus - genetics; Diabetes Mellitus - metabolism; DNA - metabolism; Endothelial Cells - metabolism; Epigenomics; Gene Expression - drug effects; Gene Regulatory Networks; Glucose - metabolism; Glucose - pharmacology; Human Umbilical Vein Endothelial Cells; Humanities and Social Sciences; Humans; multidisciplinary; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; RNA - metabolism; Science; Science (multidisciplinary); Stress, Physiological - physiology; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18957-w

Chromatin-associated RNA (caRNA) has been proposed as a type of epigenomic modifier. Here, we test whether environmental stress can induce cellular dysfunction through modulating RNA-chromatin interactions. We induce endothelial cell (EC) dysfunction with high glucose and TNFα (H + T), that mimic the common stress in diabetes mellitus. We characterize the H + T-induced changes in gene expression by single cell (sc)RNA-seq, DNA interactions by Hi-C, and RNA-chromatin interactions by iMARGI. H + T induce inter-chromosomal RNA-chromatin interactions, particularly among the super enhancers. To test the causal relationship between H + T-induced RNA-chromatin interactions and the expression of EC dysfunction-related genes, we suppress the LINC00607 RNA. This suppression attenuates the expression of SERPINE1 , a critical pro-inflammatory and pro-fibrotic gene. Furthermore, the changes of the co-expression gene network between diabetic and healthy donor-derived ECs corroborate the H + T-induced RNA-chromatin interactions. Taken together, caRNA-mediated dysregulation of gene expression modulates EC dysfunction, a crucial mechanism underlying numerous diseases. Global interaction of chromatin-associated RNAs and DNA can be identified in situ. Here the authors report the genome-wide increase of interchromosomal RNA-DNA interactions and demonstrate the importance of such RNA-DNA contacts exemplified by LINC00607 RNA and SERPINE1 gene’s super enhancer in dysfunctional endothelial cell models.