- Open position for Master thesis project – ETH Zürich (Switzerland) - RNA silencing and endomembrane system: the molecular basis of small

RNA movement in mammals

BACKGROUND MicroRNAs (miRNAs) are a class of non-coding small (s)RNAs with key regulatory roles in plants and animals. They originate from imperfect stem-loop RNA precursors, which are sequentially processed by the RNAse-III enzyme Drosha and Dicer into mature miRNAs of 19-24 nucleotides. Then, they associate with ARGONAUTE (AGO) proteins as part of RNA-induced silencing complexes (RISCs) that repress expression of mRNAs displaying miRNA sequence-complementarity.

Among the most fascinating aspects of small RNAs is their ability to cross cell boundaries. The cell-to-cell transfer of small RNA is notably crucial in in the plant A. thaliana and the worm C. elegans, where it is key for the spreading of small RNA antiviral defenses but also in stress response. We know that micro-vesicles secreted in mammalian body fluids contain small RNAs and that some small RNA effector proteins (e.g. Argonaute) can also be detected in blood serum, spurring speculations that mammalian extracellular RNAs might be biologically active upon uptake by target cells/tissues. However, the evidence of “functional transfer” of sRNAs remains scarce and the cellular mechanisms allowing their active export/ import is currently

unknown. Over the last years, our laboratory and others, established links between RNA silencing and vesicle trafficking in mammalian cells1,2,3, thereby opening the way for identifying the factors required for small RNA cell-to-cell movements. PROJECT We currently have open Master student internship positions (3- or 6- months or longer) starting from September 2014. The goal of the project is the discovery and characterization of novel endomembrane-bound proteins directly interacting with RNA silencing factors (e.g. Dicer, Argonaute). Such membrane-docking factors could notably be the key for controlling the cell-to-cell movement of extracellular RNAs in mammals. The candidate(s) will make use of the following techniques (i) plasmid cloning (ii) mammalian cell culture, (iii) live-cell fluorescent imaging, (iv) immunoprecipitation. This project is part of a novel and exciting program from the NIH on extracellular RNA (www.exRNA.org). GROUP Our group is interested in the cell biology of RNA silencing factors and the biology of extracellular RNAs. We are located in the RNA biology laboratory headed by Prof. Olivier Voinnet at ETH Zürich. The objective of the RNA biology laboratory is to characterize in detail the molecular mechanisms of RNA silencing in its various biological roles, both in plants and mammals, through a combination of genetic, biochemical, cell biology and high-throughput sequencing. Within the laboratory, consisting of a vibrant scientific community from over 10 nationalities, the working language is English. If interested, please contact Dr Bogdan Mateescu by Email (bogdanm@ethz.ch) Selected publication: 1. Gibbings D, Leblanc P, Jay F, Pontier D, Michel F, Schwab Y, Alais S, Lagrange T, Voinnet O. 2012. Human prion protein binds Argonaute and promotes accumulation of microRNA effector complexes. Nat Struct Mol Biol. 19(5):517-24 2. Gibbings D, Voinnet O. 2010. Control of RNA silencing and localization by endolysosomes. Trends in Cell Biol. 20(8):491-501 (Review) 3. Gibbings DJ, Ciaudo C, Erhardt M, and Voinnet O. 2009. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol. 11, 1143-1149.    

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