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Systematic study of post-transcriptional regulation mediated by RNA-binding proteins and miRNAs (PTRCODE)
Date du début: 1 mars 2014, Date de fin: 28 févr. 2018 PROJET  TERMINÉ 

"Post-transcriptional regulation (PTR) is increasingly recognized as a pervasive and complex system that regulates every aspect of RNA metabolism including splicing, localization, stability and translation. PTR is mediated by the interactions of trans-factors such as RNA-binding proteins (RBPs) and miRNAs with cis-acting elements located in mRNAs. Regulatory networks controlled by RBPs and miRNAs have been viewed as two distinct mechanisms; however, a number of recent studies have shown that RBPs and miRNAs can act in coordination. Previous studies of PTR have ignored this fact and only focused on a single class of factors, i.e., either RBPs or miRNAs. In this proposal, we will (i) develop computational models that consider the joint effect of multiple RBPs and miRNAs to explain PTR events (ii) integrate our PTR model with additional regulatory elements such as transcription factors, epigenetic marks and copy number changes to explain more general phenomena such as differential gene expression in cancer.Recent explosion of data in (i) RBP binding specificities, (ii) post-transcriptional fate of mRNAs (e.g. localization, stability)and (iii) mRNA-bound proteome in human cells have enabled the systematic study of post-transcriptional events, which isthe main goal of this proposal. The proposed project will start with a genome-wide mapping of binding sites of RBPs andmiRNAs in mRNAs. These potential binding sites will then be investigated for cooperative or competitive interactionsbetween RBPs and miRNAs. Independent binding sites and interactions will be converted to features, and used in statisticalmodels to identify cis-regulatory elements that are predictive of PTR events such as localization,stability, and differential gene expression in cancer. Identification of such cis-regulatory elements and their interacting trans factors will lead to new insights in disease-causing perturbations, and hence, will hopefully lead to novel approaches fortheir cure."