MicroRNA/protein interactions in the regulation of gene expression

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Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product, either a protein or an RNA. The regulation of gene expression is an ensemble of phenomena by which the genetic code is interpreted to give rise to the properties of cells, organs and organisms. Several recent discoveries have led to the idea that RNA is a master regulator of gene expression. One of the most important discoveries linking RNA to gene regulation was that of RNA interference, for which Mello and Fire were awarded the 2006 Nobel Prize in Medicine. RNA interference involves small non-coding RNAs called microRNAs (miRNAs) that constitute one of the largest families of transacting gene regulatory molecules in multi-cellular organisms. It is well known that mammalian miRNAs largerly target mRNAs from developmental genes and that their misregulation is linked to various diseases, in particular several forms of cancers. However, the regulatory networks involving miRNAs and their role in cancer development are only starting to be understood. Recent studies demonstrate that the precursor forms of some miRNAs are specifically recognized by proteins to enable regulation of miRNA-dependent gene expression. The long-term objective of our research program is to functionally and structurally characterize how specific protein / miRNA interactions regulate miRNA-dependent cellular processes. Among those miRNAs that have been associated with cellular differentiation and cancer, miRNAs from the let 7 family have been the most thoroughly investigated. Previous studies have demonstrated that the let-7g biogenesis is controlled post-transcriptionally and that the Lin28 protein is responsible for this regulation through direct interactions with the immature forms of the let 7g miRNA. Our short-term goal is to characterize specific interactions involving the Lin28 protein and the let 7g miRNA. Our structural and functional studies of the Lin28 / pre-let-7g complex will provide critical and timely insights to our understanding of miRNA biogenesis and activity. Given the role of the let-7 miRNA in tumor suppression, our studies could also enable the development of novel cancer therapeutics.