The cardiac lncRNA Chantico directly regulates Cxcl1 chemokine transcription

Abstract

SummaryIn local gene regulation, long noncoding RNA (lncRNA) loci can function at three distinct, but non-mutually exclusive levels: the RNA molecule itself, the process of its transcription, and/or the underlying DNA element. Yet for cis-acting lncRNA, these distinctions are particularly challenging with present tools. To address this problem, we developed Omegazymes, catalytic nucleic acid enzymes to specifically target lncRNA for degradation without triggering premature termination of their transcription. We use Omegazymes to selectively target one of a highly refined set of lncRNAs in the mouse cardiomyocytes, demonstrating that the Chantico lncRNA molecule directly potentiates the transcription of Cxcl1, a neighboring chemokine gene. We find that the Chantico locus also acts at the DNA-level, as the binding of an essential cardiac transcription factor to the Chantico promoter is necessary for Cxcl1 transcription in mature cardiomyocytes. This Chantico regulation of Cxcl1 impacts cardiomyocyte signaling to immune cells, potentially regulating tissue-residence and inflammation.