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RNA Regulatory Networks

in the Brain

MicroRNAs (miRNAs) are a class of single-stranded RNAs (ssRNAs), 19-25 nucleotides (nt) in length. They control the expression levels of their target genes through an imperfect pairing with target messenger RNAs (mRNAs), mostly in their 3' untranslated regions (3' UTRs). miRNAs are implicated in a wide range of basic biological processes and human diseases. Given that the brain, in both mice and humans, expresses a large spectrum of distinct miRNAs that other organs, it is likely that dysregulation of miRNA networks has an outsized effect on neurological function. The challenge is identifying each miRNA's set of target genes. Existing methods each operate under certain assumptions, and each arrives at a different set of targets, with little overlap among different tools. We demonstrated that it is possible to identify miRNA target genes by looking at their patterns of expression, and we developed two tools that outperform other current tools in the identification of miRNA targets: HOCTAR (Genome Research, 2009; Gene, 2011) and CoMeTa (Genome Research, 2012). Both tools have been already used to identify miR-128 in controlling the lysosomal master gene TFEB (Science, 2009) and miR-483-5p, which regulate the levels of MECP2, the gene mutated in Rett syndrome (Genes & Development, 2013).  The next challenge will be to characterize, in vivo, individual miRNAs and specific families of miRNAs that are predicted to contribute to the proper CNS function to find new candidate key-disease driving genes in human.

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