Stress-induced RNA-chromatin interactions promote endothelial dysfunction.

Area of Science:

• Epigenetics and Molecular Biology
• Cellular Biology
• Genomics

Background:

• Chromatin-associated RNA (caRNA) is implicated as an epigenomic modifier.
• Environmental stressors can impact cellular function through epigenetic mechanisms.
• Endothelial cell (EC) dysfunction is a hallmark of diseases like diabetes mellitus.

Purpose of the Study:

• To investigate if environmental stress modulates RNA-chromatin interactions to induce EC dysfunction.
• To elucidate the role of caRNA in stress-induced cellular dysfunction.
• To identify specific RNA-chromatin interactions involved in EC dysfunction.

Main Methods:

• Endothelial cells were exposed to high glucose and TNFα (H+T) to mimic diabetic stress.
• Single-cell RNA sequencing (scRNA-seq) characterized gene expression changes.
• Hi-C and iMARGI were used to analyze DNA-DNA and RNA-chromatin interactions, respectively.
• LINC00607 RNA was suppressed to assess its causal role.

Main Results:

• H+T treatment induced inter-chromosomal RNA-chromatin interactions, particularly at super enhancers.
• Suppression of LINC00607 RNA attenuated the expression of the pro-inflammatory gene SERPINE1.
• Analysis of co-expression gene networks in diabetic versus healthy ECs supported the role of RNA-chromatin interactions.

Conclusions:

• Chromatin-associated RNA-mediated gene dysregulation is a significant factor in endothelial cell dysfunction.
• Modulation of RNA-chromatin interactions represents a crucial mechanism underlying stress-induced cellular dysfunction.
• Targeting caRNA interactions may offer therapeutic strategies for diseases associated with EC dysfunction.