MIREG · Regulation of viral miRNAs processing

Regulation of viral miRNAs processing

The discovery of RNA interference in plant and Caenorhabditis elegans, and all related RNA silencing processes, was one of the major breakthroughs in modern biology. The most abundant and studied eukaryotic regulatory RNAs are microRNAs (miRNAs, ≈20 nucleotides long). They control fundamental processes such as development, immunity, oncogenesis, etc. In human, they represent ≈1% of the genes and may control more than 30% of the genome. Recently, viruses infecting mammalian cells (mostly of the herpes family) have been shown to express their own miRNAs. Although the mode of action of miRNAs is well known, the principles governing their expression and activity are only beginning to emerge. Indeed, miRNA biogenesis is a complex and highly regulated process. My reintegration period under Marie Curie fellowship allowed me to develop a new project in S. Pfeffer’s lab, named “Non-coding RNAs and viral infections”. My research focused on the expression of a cluster of 12 miRNAs encoded by Kaposi’s sarcoma associated herpesvirus (KSHV). KSHV is an oncogenic human virus, causing severe disease like Kaposi’s sarcoma and lymproliferative disorders. Its miRNAs are expressed in the cancer lesions and are important to maintain latency, to inhibit apoptosis and to regulate the host cell cycle. We show that they accumulate at various levels in the cells and this was dependent on the cellular context. In addition, we determined the secondary structure of the long primary transcript (pri-miRNA) leading to the many mature miRNAs. We could directly correlate specific structural features of the pri-miRNA to the relative abundance of the mature miRNAs in cells. We suggest that this is mainly due to the structural impact on the first maturation step executed by the enzyme Drosha. We also explore the requirement of protein co-factors for this step. In the long range, our study may open the way to the understanding of miRNA expression of other viruses. Up to 15-20 % of cancers are caused by infectious agents and most of these by viruses. Recently, viral miRNAs have been identified as crucial players in the pathogenesis and the survival of some viruses. Moreover, it is now well documented that modulation of miRNA expression may be linked to cancer development. These small regulators may represent ideal targets for drug therapy. Thus, any knowledge on how this miRNAs are expressed and regulated in the infected cells is of high impact for medical research. Finally, I consider that my reintegration period was successful both scientifically and for my career development. The grant helped me substantially to settle in the lab and to develop my project, by covering most of the costs. This directly impacted on my research achievements and enhanced my competitiveness. As a result, I obtained in October 2012, after national competition, a permanent academic research position within the CNRS. It allows me to envisage my scientific career and my research project in the long term with serenity, in the host institution I chose for its excellence and expertise in the domain of RNA function and structure.

Data: CORDIS, © European Union