Transcriptome-wide Discovery of microRNA Binding Sites in Human Brain

• Ago2 HITS-CLIP reveals miRNAs and their transcriptomic binding sites in human brain
• >1,800 Ago2 binding sites correspond to the top 20 most abundant human brain miRNAs
• Conserved human and mouse brain Ago binding sites associate with synaptic functions
• Ago2 binding sites overlap disease-relevant polymorphisms that alter miRNA seed pairing

SummaryThe orchestration of brain function requires complex gene regulatory networks that are modulated, in part, by microRNAs (miRNAs). These noncoding RNAs associate with argonaute (Ago) proteins in order to direct posttranscriptional gene suppression via base pairing with target transcripts. In order to better understand how miRNAs contribute to human-specialized brain processes and neurological phenotypes, identifying their targets is of paramount importance. Here, we address the latter by profiling Ago2:RNA interactions using HITS-CLIP to generate a transcriptome-wide map of miRNA binding sites in human brain. We uncovered ∼7,000 stringent Ago2 binding sites that are highly enriched for conserved sequences corresponding to abundant brain miRNAs. This interactome points to functional miRNA:target pairs across >3,000 genes and represents a valuable resource for accelerating our understanding of miRNA functions in brain. We demonstrate the utility of this map for exploring clinically relevant miRNA binding sites that may facilitate the translation of genetic studies of complex neuropsychiatric diseases into therapeutics.