ABCA1-eRNA as a novel Epigenetic Regulator, promotes cholesterol efflux, Attenuates Macrophage Inflammation and Severity of Coronary Artery Disease [ATAC-seq]

Enhancer RNAs (eRNAs) are emerging as powerful regulators of various biological processes, but the underlying epigenetic regulatory mechanisms of these molecules in cholesterol homeostasis remain elusive. Using an integrated genomic screen, we identified an intragenic super-enhancer derived long noncoding RNA embedded in the ATP-binding cassette transporter A1 (ABCA1) gene, named ABCA1-seRNA, which is required for activation of RXRα/LXR mediated gene expression. Deficiency of ABCA1-seRNA abolished cholesterol efflux, promotes Macrophage Inflammation, and that haven been causally Susceptibility to Coronary heart disease. Mechanistically, ABCA1-seRNA affects cholesterol efflux by interaction with MED23 and recruitment RXR and LXR to mediate ABCA1 transcription in cis. Furthermore, ABCA1-seRNA repression inflammatory response and attenuated macrophage M1 polarization and migration through ubiquitination of a NF-B subunit P65. Our results suggest that super-enhancer derived long noncoding RNA, as a novel Epigenetic Regulator, are critical components to maintain cholesterol homeostasis and inflammation restriction, represent an attractive therapeutic target to reduce Atherosclerotic cardiovascular disease (ASCVD).