Stress-induced RNA–chromatin interactions promote endothelial dysfunction

Riccardo Calandrelli, Lixia Xu, Yingjun Luo, Weixin Wu, Xiaochen Fan, Tri Nguyen, Chien-Ju Chen, Kiran Sriram, Xiaofang Tang, Andrew B. Burns, Rama Natarajan, Zhen Bouman Chen () and Sheng Zhong ()
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Riccardo Calandrelli: University of California San Diego
Lixia Xu: Guangdong Academy of Medical Sciences
Yingjun Luo: Beckman Research Institute, City of Hope
Weixin Wu: University of California San Diego
Xiaochen Fan: University of California San Diego
Tri Nguyen: University of California San Diego
Chien-Ju Chen: University of California San Diego
Kiran Sriram: Beckman Research Institute, City of Hope
Xiaofang Tang: Beckman Research Institute, City of Hope
Andrew B. Burns: Beckman Research Institute, City of Hope
Rama Natarajan: Beckman Research Institute, City of Hope
Zhen Bouman Chen: Beckman Research Institute, City of Hope
Sheng Zhong: University of California San Diego

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-18957-w

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