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Julien Béthune 
Posttranscriptional regulation of mRNA expression and localization

Gruppenleiter: Julien Béthune

Posttranscriptional regulation of mRNA expression and localization

Misregulation of gene expression and mRNA localization is a source of numerous diseases, notably cancer and neurological disorders. Our group is interested in the mechanisms of posttranscriptional gene silencing, notably by miRNAs, as well as in the interplay between membrane trafficking and mRNA regulation and localization in mammalian cells. More specifically, our research focuses on the two following directions:

1) Mechanism of miRNA-mediated gene silencing. miRNAs are small non-coding RNAs that have emerged as key regulators of most cellular functions by posttranscriptionally repressing at least 50% of expressed mRNAs. Loaded onto an argonaute protein, they serve as guide by base-pairing with target mRNAs to recruit an RNA-induced silencing complex (miRISC) which both represses translation and induces mRNA decay. While most mRNA targets of miRNAs end up being degraded at steady-state, others are kept stable in a silent state, possibly until an appropriate stimulus reverses silencing. The latter is of particular importance in polarized cells such as neurons where miRNAs are suggested to play a role in mRNA transport and localized translation. To date it is poorly understood how certain miRNA targets escape degradation while staying in a translationally repressed state. Previous work suggests that this is mediated by cis-regulatory elements recruiting trans-acting factors that we aim to identify and characterize.

2) Interplay between membrane and mRNA transport. Specific RNA and protein localization is essential to maintain polarity and normal function of virtually all cell types. Membrane-enclosed transport vesicles mediate protein and lipid transport within the secretory pathway, from the ER to the plasma membrane. A surprising and largely unexplored link between mRNA and vesicular transport has been suggested by several studies. An emerging picture is that small vesicular carriers may also transport and help localizing silenced-mRNAs, and thus add another layer of regulation to gene expression. We now aim at characterizing the mechanisms underlying the recruitment and silencing of specific mRNAs to specific transport vesicles using a combination of cutting-edge molecular biology, biochemistry and imaging approaches.

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