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 gene ANRIL associated with coronary artery disease (CAD) play antagonizing roles against each other. We previously reported that DQ485454, 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 transcript NR_003529 is significantly upregulated in coronary arteries from CAD patients. Overexpression of ANRIL transcript NR_003529 increases monocyte adhesion to ECs and TEM, whereas knockdown of NR_003529 expression reduces monocyte adhesion to ECs and TEM. Much more dramatic effects were observed for the combination of overexpression of NR_003529 and knockdown of DQ485454 or the combination of knockdown of NR_003529 and overexpression of DQ485454. The antagonizing effects of ANRIL transcripts NR_003529 and DQ485454 were associated with their opposite effects on expression of downstream target genes EZR, CXCL11 or TMEM106B. 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 that ANRIL is the causative gene at the 9p21 CAD susceptibility locus.

每个基因通常具有多个交替剪接的转录本。假定不同的转录本起着相似的生物学作用；但是，某些转录本可能会由于失去重要的功能域而直接丧失其功能。在这里，我们显示与冠心病（CAD）相关的lncRNA基因ANRIL的两个不同的转录本相互之间起着拮抗作用。我们之前曾报道过，短转录本DQ485454在CAD患者的冠状动脉中被下调，并减少了单核细胞与内皮细胞（ECs）的粘附和跨内皮单核细胞迁移（TEM）。有趣的是，最长的转录本NR_003529在CAD患者的冠状动脉中显着上调。ANRIL的过表达转录本NR_003529增加单核细胞对EC和TEM的粘附，而NR_003529表达的降低会降低单核细胞对EC和TEM的粘附。多观察到更显着的效果对于过表达的组合NR_003529和敲低的DQ485454或敲除的组合NR_003529和过表达DQ485454。ANRIL转录本NR_003529和DQ485454的拮抗作用与其对下游靶基因EZR，CXCL11或TMEM106B表达的相反作用相关。我们的结果表明，lncRNA的不同转录本可以对生物学功能发挥拮抗作用，从而为lncRNA的生物学研究提供重要见解。数据进一步支持以下假设：ANRIL是9p21 CAD易感基因位点的致病基因。