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Stress-induced RNA-chromatin interactions promote endothelial dysfunction.

  • Author(s): 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
  • et al.
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.

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