Abstract 20207: Deciphering and Exploiting MicroRNA-Target Interactomes in Human Cardiac Tissues
The orchestration of complex biological functions requires gene regulatory networks that are modulated, in part, by microRNAs (miRNAs). During the past decade, miRNAs have emerged as key biological effectors, and growing evidence indicates that miRNAs play critical roles in an array of human diseases, including cardiovascular conditions. These noncoding RNAs associate with Argonaute proteins (e.g. Ago2) to direct post-transcriptional gene suppression via base-pairing with target transcripts. To better understand how miRNAs contribute to protective and pathogenic responses to disease, identifying their targets in affected tissues is of paramount importance. Here, we addressed the latter by profiling Ago2:RNA interactions using crosslinking immunoprecipitation coupled with high-throughput sequencing (CLIP-seq) to generate the first transcriptome-wide map of miRNA binding sites in human heart tissues (normal and failing, n=4 each). We uncovered thousands of Ago2 binding sites which are highly enriched for conserved sequences corresponding to abundant cardiac miRNAs. This interactome provides a valuable resource for accelerating our understanding of miRNA functions in the cardiovascular system. Notably, our initial exploration of these data has revealed numerous clinically-relevant interactions involving miRNAs and target genes previously implicated in cardiomyopathies (e.g. miR-1, -23, -24, -29, -208, Serca2, Ryr2, CaMKII, among others). Also, the interactome points to a coordination of miRNA activities in controlling calcium handling and signaling, mitochondrial function, and metabolic signaling pathways. Overall, this work represents an initial step towards characterizing the diverse landscape of miRNA:target interactions across normal and diseased human cardiac tissues, and the primary data offers clues which may facilitate the translation of genetic studies of complex cardiovascular-related diseases into novel or refined pathogenic mechanisms and therapeutics.
Author Disclosures: C. Cheng: None. R.M. Spengler: None. F.L. Johnson: None. S.G. Drakos: None. D.Y. Li: None. N. Diakos: None. B.L. Davidson: None. R.L. Boudreau: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.