Abstract 456: LncRNA CHROME is Increased in Cardiovascular Disease and Regulates Inflammatory Gene Expression

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 38; no. Suppl_1
• Main Authors: Scacalossi, Kaitlyn R, van Solingen, Coen, Hennessy, Elizabeth J, Rizzacasa, Barbara, Berger, Jeffrey S, Kazan, Hilal, Moore, Kathryn J
• Format: Journal Article
• Language: English
• Published: 01.05.2018
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/atvb.38.suppl_1.456

Abstract only Long non-coding RNAs (lncRNAs) are a class of regulatory RNAs capable of binding DNA, RNA, and/or protein to regulate transcriptional and epigenetic networks. Although thousands of lncRNAs have been identified, relatively few have been functionally characterized. Here we identify a primate-specific lncRNA, CHROME , encoded in a locus associated with cardiovascular disease. We found that CHROME expression is increased in the plasma of patients with inflammatory conditions, including coronary artery disease and lupus, compared to control subjects. Using FANTOM, a database of transcriptome analyses, we found the CHROME locus is transcriptionally activated in human monocytes and macrophages stimulated with microbial ligands and inflammatory cytokines. To investigate CHROME’s molecular mechanisms, we used RNA immunoprecipitation (RIP) and chromatin isolation by RNA purification (ChIRP) to map CHROME lncRNA -protein and -DNA interactions, respectively. We found that CHROME has a strong histone binding affinity and its DNA binding pattern was consistent with interaction of CHROME with numerous inflammatory transcription factor motifs, including sites for CEBPβ, SPI1, NFKB, and RELA. To investigate the impact of CHROME’s interaction with DNA in macrophages, we used gain and loss of function studies combined with RNA-sequencing. Ingenuity Pathway Analysis of genes most significantly altered with both CHROME knockdown and overexpression identified the inflammatory response as the pathway most significantly altered by CHROME . In particular, repression of CHROME led to a decrease in the expression of interferon stimulated genes and receptors involved in macrophage motility. Together, these data suggest that CHROME contributes to the transcriptional regulation of inflammatory gene expression and its dysregulation in the setting of atherosclerotic cardiovascular disease may contribute to the maintenance of chronic inflammation.