M6Abolic-RNA-duplex · Metabolic control of RNA-protein and RNA-RNA interactions in cellular transformation.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-09-01 → 2018-08-31
- EU contribution
- €195,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
Metabolic control of RNA-protein and RNA-RNA interactions in cellular transformation.
What is the problem being addressed? In this project, we proposed to study RNA methylation as a ‘dynamic’ and ‘regulatory mechanism’ of RNA structure, RNA-protein assembly and, therefore, RNA function. It is now known that N6-methyladenosine is a RNA modification with key roles in cell differentiation and development. Yet, there is limited insight on the 'upstream' regulatory mechanisms of m6A marks that lead to cell fate transitions, and whether other RNA modifications are regulated in a similar fashion is unexplored. In this context, this research was designed to approach the ‘metabolic dependencies’ of RNA methylation in order to elucidate the ‘dynamics’ and ‘function(s)’ of RNA methylation in cell differentiation and proliferation. This project has been focused in 786O cancer cells and two models of cell differentiation: CD8+ T-cells and mouse embryonic stem cells (mESCs). Why is it important for society? At the completion stage, this project is expected to provide far-reaching insights on fundamental regulatory mechanisms of RNA function, and it may lead to the development of new methodologies in: i) Regenerative medicine, aimed at the control of cellular pluripotency/differentiation; ii) Immunotherapy, aimed at the efficacy of T-cell differentiation into central/effector memory T-cells, and/or metabolic treatments in T-cell homeostasis; iii) Cancer cell biology, aimed at targeting RNA methylation What are the overall objectives? (Initial objectives were updated as below due to project advancement and methodologies developed in the host lab) Objective 1: Metabolic and cell differentiation states associated with ‘hyper’- or ‘hypo’-methylated RNAs - achieved Objective 2: Transcriptome-wide profile of RNA methylation in cell differentiation and metabolic states associated with ‘hyper’ or ‘hypo’ methylation – partially achieved Objective 3: Elucidate the role of RNA methylation in the structure and function of ‘dynamic’ RNAs (objective 1) – partially achieved Objective 4: Significance of RNA methylation in cell fate transitions and cancer cell proliferation – ongoing
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- UNIVERSITY COLLEGE LONDON · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union