RNA Biology - O. Voinnet

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Our laboratory focuses on various aspects of a highly conserved mechanism called “RNA silencing”, which encompasses many processes in which tiny RNA molecules (20-30 nt long) are used as guides to promote nucleotide sequence-specific regulations at the levels of mRNA stability and translation, and, in some organisms, at the level of DNA methylation and chromatin modification.

More specifically, we are interested in understanding the biogenesis, modes of action and biological functions of two main classes of cellular small RNAs that are both processed from double-stranded RNA precursors by RNase III-like enzymes in the Dicer family, and loaded into Argonaute (AGO) proteins that effect their activity at the RNA and DNA levels, as part of RNA-induced silencing complexes (RISCS).

A first class of molecules, called microRNAs (miRNAs), controls many aspects of biology in plants and in metazoans, including humans. The processes controlled by miRNAs range from developmental patterning, maintenance of cellular identity, to stress adaptation, while defects in miRNAs biogenesis or function underpin several major genetic disorders and have been correlated to cancer. Over the years, our laboratory has undertaken reverse genetic, biochemical and cell biological approaches to understand the tenets of miRNA biology, mostly focusing on the model plant species Arabidopsis thaliana. More recently, we have additionally developed powerful systems based on plant cell-free extracts, novel biochemical fractionation methods for AGO proteins, and single-cell resolution analyses conducted in planta to complement these approaches. Our interest in miRNAs extends to mammalian models where we are investigating the possibility that these molecules might be functionally secreted from, and transported between, cells. Additionally, we are investigating the ways by which AGO proteins are regulated in these cells.

The second class of small RNAs that is of interest to our laboratory is encompassed by the small interfering RNAs (siRNAs). In plants, fungi and some invertebrates, vast amounts of endogenous siRNAs are synthesized from double-stranded RNA derived from transposons and repeats. siRNAs guide DNA methylation or histone tail modifications at these repeats to dampen their transcriptional activity and, under circumstances, mobility. In this framework, we are trying to understand the processes by which Arabidopsis transposable elements are primarily recognized as foreign molecules by the siRNA machinery, and the course of molecular events that ultimately leads to their silencing.

A second category of siRNAs acts at the post-transcriptional level to mediate RNA degradation and these are abundantly produced during virus infections of plants and invertebrates, where they convey sequence-specific immunity upon their loading into antiviral AGO proteins. Our laboratory is interested in deciphering the molecular basis for this antiviral silencing in plants. We are also exploring possibilities that virus-derived siRNAs might mediate immunity in at least some mammalian cell types. In plants and some invertebrates, RNA silencing mediated by siRNAs of viral or endogenous origin has the remarkable ability to move from cell-to-cell and over long-distances from its sites of initiation, a phenomenon that likely constitutes the systemic arm of antiviral RNA silencing and may also contribute to long-distance genetic and epigenetic gene regulation as well as trans-generational inheritance. Our laboratory is deeply involved in understanding the various aspects of non-cell autonomous RNA silencing as well as its biological relevance in plant immunity, growth and reproduction.

 
 
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