Objective In the current paradigm of gene expression, the structure of messenger RNA (mRNA) is a key element of posttranscriptional control because it modulates interactions with RNA-binding proteins (RBPs). RBPs typically recognize RNA-binding domains to form ribonucleoprotein complexes that ‘commit’ mRNAs to specific functions, and mutated or deregulated RBPs are implicated in multiple neurodegenerative diseases and cancer. Yet, the knowledge on the dynamic regulation of ribonucleoprotein complexes in mammalian cells is limited, mostly because the ‘structure’ and ‘specificity’ of RNA-protein interactions are amply unexplored. Recently, the host laboratory developed a new technique – hiCLIP – which identifies the transcriptome-wide RNA secondary structures (RNA duplexes) bound by particular RBPs, paving the way for pioneering research on the ‘structural determinants’ of RNA function in mammalian cells. In this context, N6-methyladenosine (m6A) is the most prevalent internal modification in mRNAs with critical functions in RNA stability, and seminal studies recently showed that m6A ‘marks’ destabilize in vivo RNA duplexes in the mammalian transcriptome. However, i) how m6A ‘marks’ regulate RNA-protein interactions that rely on RNA secondary structures is unknown, and ii) there is no systems-level elucidation of which RBPs are sensitive to m6A. Importantly, the ‘maintenance’ of m6A levels requires metabolic substrates and the m6A protein machinery is implicated in obesity and cancer. Collectively, these evidences point to a structural role of m6A in RNA function, and raise the compelling notion that metabolic control of m6A may represent a ‘regulatory module’ of gene expression in mammalian cells. The research proposed herein is designed to reveal the ‘regulatory principles’ of RNA structures in cell physiology, and the prospective results are likely to provide far-reaching insights on the significance of this process for metabolism-related diseases and cancer. Fields of science medical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticsRNAmedical and health sciencesbasic medicineimmunologyimmunotherapymedical and health scienceshealth sciencesnutritionobesity Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Call for proposal H2020-MSCA-IF-2015 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator UNIVERSITY COLLEGE LONDON Net EU contribution € 195 454,80 Address GOWER STREET WC1E 6BT London United Kingdom See on map Region London Inner London — West Camden and City of London Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 195 454,80
