Abstract 18910: Deciphering and Exploiting Transcriptome-Wide MicroRNA Binding Profiles in Human 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 neurological and cardiovascular conditions. These noncoding RNAs associate with Argonaute (Ago) proteins 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. As an initial step towards addressing the latter, we profiled 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 a human primary tissue, the brain. We uncovered ~7000 stringent Ago2 binding sites which are highly enriched for conserved sequences corresponding to abundant brain miRNAs. This dataset points to functional miRNA:target pairs across more than 3000 genes and represents a valuable resource for accelerating our understanding of miRNA function in the central nervous system, and beyond. We explored this interactome for clinically-relevant miRNA binding sites and discovered sites overlapping single nucleotide polymorphisms linked to common and rare neuropsychiatric conditions, including Parkinson’s and Alzheimer’s. In addition, we identified nearly 50 miRNA target sites across 20 genes previously implicated in stroke and arterial disease. These findings provide clues which may facilitate the discovery of novel and refined pathogenic mechanisms and therapeutics for complex diseases of the brain and vasculature. Overall, this work lays the foundation for translating this methodology to characterize the diverse landscapes of miRNA:target interactions across normal and diseased human tissues, particularly heart, where miRNAs are well-established mediators of cardiac development and disease.
- © 2013 by American Heart Association, Inc.