ABCA1-Super Enhancer RNA Promotes Cholesterol Efflux, Reduces Macrophage-Mediated Inflammation and Atherosclerosis
Jing Wang, Qianqian Xiao, Yuwei Cai, Man Wang, Chen Chen, Luyun Wang, Ruiying Ma, Yanyan Cao, Yan Wang, Hu Ding, Dao Wen Wang
Abstract
• ABCA1-seRNA was identified as a novel super-enhancer RNA. • ABCA1-seRNA positively regulates ABCA1 expression by recruiting mediator (MED23) and transcriptional factor (RXRα and LXRα). • ABCA1-seRNA negatively regulates NF-κB activation by ubiquitination degradation P65. • ABCA1-seRNA involves in the constitute of chromatin loops and it also relies on the loop to produce effects on anti-atherosclerosis. We describe a previously uncharacterized ATP-binding cassette A1 super enhancer RNA (ABCA1-seRNA)-mediated cholesterol efflux. In addition, it promoted macrophage inflammatory cytokine release, and was causally correlated with coronary artery disease severity. Mechanistically, ABCA1-seRNA upregulated cholesterol efflux by interacting with mediator complex subunit 23 and recruiting retinoid X receptor-alpha and liver X receptor-alpha to promote ABCA1 transcription in a cis manner. Meanwhile, ABCA1-seRNA induced P65 ubiquitination degradation, and thereby repressed the macrophage inflammatory response. Consistently, overexpression of ABCA1-seRNA in ApoE −/− mice decreased plasma lipids, cytokines, and atherosclerotic plaques. These findings indicate ABCA1-seRNA is a critical epigenetic regulator that maintains cholesterol homeostasis and modulates inflammation, thus promising a therapeutic target for atherosclerotic cardiovascular diseases.