Abstract 3050: The Multifaceted Roles Of Long Noncoding Rna CHROMR In Cardiovascular Disease

Abstract

The last decade revealed powerful roles for long noncoding RNA (lncRNA) in chromatin organization and orchestration of gene expression in healthy and pathological states, including atherosclerotic cardiovascular disease (ACVD). Yet, fewer than 10% of human lncRNAs have been characterized, representing unique opportunity for discoveries in the pathogenesis and treatment of ACVD. We previously showed that the primate-specific lncRNA CHROMR (CHolesterol-induced Regulator Of Metabolism RNA) is induced by cholesterol excess to restrict the availability of functionally related microRNAs that normally repress cholesterol efflux and HDL biogenesis. Using single-cell RNA-seq analysis of human carotid plaques from the NYU ATHERO-IN study, we now show that CHROMR is robustly expressed in myeloid cells within carotid plaques and strongly correlates with expression of interferon (IFN) stimulated genes (ISGs). Previously we established that CHROMR functions in the nucleus to license the expression of interferon (IFN) stimulated genes (ISGs). CHROMR acts through sequestering IFN regulatory factor-2 binding protein 2, part of the IRF2 repressor complex that antagonizes transcriptional activation of ISGs. While this coordinated regulation of lipid metabolism and IFN responses by CHROMR is beneficial in accelerating an inflammatory response upon viral infection, it has detrimental effects in the context of ACVD. As such, therapeutic inhibition of CHROMR holds potential to reduce plaque inflammation. Therefore, we treated human atherosclerotic 3D carotid vascular explants with GapmeRs to deplete CHROMR and subsequently measured the cellular response upon inflammatory stimulus. We found that Gap CHROMR reduced CHROMR levels and blunted pro-atherogenic cytokine/chemokine secretion, whereas lentiviral delivery of CHROMR increased cytokine/chemokine secretion when compared to controls. Collectively, our findings underscore the merit of investigating CHROMR, as well as other lncRNAs, to decipher novel regulatory mechanisms that govern lipid metabolism and inflammation in humans.