UC San Diego

The let-7 miRNA is a highly conserved regulatory molecule that dictates development across animal phyla, and mis- regulation of let-7 in humans results in numerous diseases. In order to unravel the complex mechanisms involved in the biogenesis of the let-7 microRNA (miRNA), my research has focused on three areas: transcriptional regulation of primary let-7 (pri-let-7) throughout development, post-transcriptional regulation of pri-let-7 by the LIN-28 protein during early developmental stages, and post-transcriptional regulation of pri-let-7 during later developmental stages by the mature let-7 miRNA and ALG-1 protein (Argonaute Like Gene 1). In the first, and primary, area of my research--transcriptional regulation of let-7--I have discovered a novel cis-element in the promoter of the let-7 gene, trans-acting factors regulating the spatio-temporal specificity of pri-let-7 transcription and a dynamically cycling transcriptional expression regulated in the molting pathway. Investigating post-transcriptional regulation of let-7 biogenesis, I collaborated with Dr. Priscilla Van Wynsberge and we found that LIN-28, a highly conserved RNA binding protein, co- transcriptionally associates with pri-let-7 to negatively regulate pri-let-7 biogenesis. Working with Dr. Dimitrios G. Zisoulis, we discovered that the let-7 miRNA guided miRISC (miRNA Induced Silencing Complex) with the ALG-1 protein, directly binds and positively regulates maturation of pri-let-7 transcripts in a novel auto- regulatory feedback loop that is conserved across species. This is the first report of the miRISC complex targeting a primary miRNA transcript. This auto-regulatory model of miRNA maturation provides a novel role for ALG-1 as well as let-7 and introduces a new mechanism of miRNA regulation