Title: Regulation of miRNA Biogenesis and Function in Humans
Funder: Medical Research Council

Abstract: In recent years, microRNA molecules have emerged as fundamental players in the biology of many living organisms MicroRNAs (miRNAs) constitute a family of short (21-23nt), non-coding RNAs that regulate gene expression and control a variety of biological processes. Given their diverse functions, it is not surprising that the spatial and temporal regulation of their expression is tightly regulated. Aberrant miRNA expression is linked to a wide variety of human pathological states including initiation, progression and metastasis of human cancers. Moreover, miRNAs are seen as promising tools for rational, target mRNA-based therapy. Thus, thorough knowledge of their functions and biogenesis pathways will be instrumental in pursuing such therapeutic approaches. Mature miRNAs are derived from primary transcripts (pri-miRNA) by sequential nuclear and cytoplasmic processing events. They are transcribed as individual pri-miRNAs or in the clusters of pri-miRNAs grouped together. In the nucleus, microprocessor complex containing drosha and its RNA-binding partner DGCR8 generates stem-loop precursors (pre-miRNA), which are exported to the cytoplasm. In the cytoplasm, Dicer cleaves off the pre-miRNA loop leaving miRNA duplex. Subsequently, one strand of this duplex is incorporated into RNA-Silencing Complex (RISC), which targets specific mRNAs and controls their expression by affecting either transcript stability or translation. Although some of the principle steps in the biogenesis of microRNAs have emerged in recent years, our understanding of how post-transcriptional processing of microRNAs is regulated remains rudimentary. I have recently found that hnRNP A1, a protein implicated in many aspects of RNA processing, acts as an auxiliary factor for the drosha-mediated processing of a miRNA precursor, pri-miR-18a, by binding to its conserved terminal loop and reshaping the stem loop structure. This suggested a previously uncharacterized role for general RNA binding proteins as auxiliary factors that control the biogenesis of specific miRNAs. The aim of my project is to study regulation of miRNA biogenesis and function in humans. The main objectives are: 1) to identify a network of miRNAs that are regulated by hnRNP A1; 2) to elucidate the regulatory mechanism of neuronal-enriched miRNAs biogenesis; 3) to identify the auxiliary factors that control the production of miRNAs present in pri-miRNA clusters; 4) to test the hypothesis that pre-miRNAs stem-loops are directly involved in the regulation of gene expression. The methodology for the proposed research is based on functional studies of RNA, RNA structure determination, cell biology, protein-RNA and protein-protein interactions analysis. Proposed projects represent novel concepts in the fields of miRNA and gene expression regulation. I believe that my research can contribute towards better understanding of gene expression regulation in normal states and pathological conditions in humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE