Splice variants of lncRNA RNA ANRIL exert opposing effects on endothelial cell activities associated with coronary artery disease

Each gene typically has multiple alternatively spliced transcripts. Different transcripts are assumed to play a similar biological role; however, some transcripts may simply lose their function due to loss of important functional domains. Here, we show that two different transcripts of lncRNA geneANRILassociated with coronary artery disease (CAD) play antagonizing roles against each other. We previously reported thatDQ485454, the short transcript, is downregulated in coronary arteries from CAD patients, and reduces monocyte adhesion to endothelial cells (ECs) and transendothelial monocyte migration (TEM). Interestingly, the longest transcriptNR_003529is significantly upregulated in coronary arteries from CAD patients. Overexpression ofANRILtranscriptNR_003529increases monocyte adhesion to ECs and TEM, whereas knockdown ofNR_003529expression reduces monocyte adhesion to ECs and TEM. Much more dramatic effects were observed for the combination of overexpression ofNR_003529and knockdown ofDQ485454or the combination of knockdown ofNR_003529and overexpression ofDQ485454. The antagonizing effects ofANRILtranscriptsNR_003529andDQ485454were associated with their opposite effects on expression of downstream target genesEZR, CXCL11orTMEM106B. Our results demonstrate that different transcripts of lncRNA can exert antagonizing effects on biological functions, thereby providing important insights into the biology of lncRNA. The data further support the hypothesis thatANRILis the causative gene at the 9p21 CAD susceptibility locus.