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Epitranscriptomics at the crossroads of metabolism and cellular ageing

Project description

Reversible RNA modifications could be a target to treat metabolic disorders and ageing

DNA methylation (5mC) and hydroxymethylation (5hmC), the addition of a methyl group or its oxidation, are common epigenetic mechanisms essential for gene regulation. Recently, 5hmC mediated by Ten–eleven translocation-2 (TET2) enzymes has been linked with epigenetic regulation in the brain and liver, with implications for cellular ageing, cognitive function and metabolism. Interestingly, TET2 has also recently been shown to 5hmC-modify RNA. The EU-funded EpiMetAgeing project is investigating the potential role of TET2-mediated 5hmC in RNA in ageing and obesity, more specifically in obesity as age progresses. Given that RNA modifications are reversible, their characterisation could also provide a target for therapies for obesity, ageing and age-related metabolic disorders.

Objective

Ageing is an unavoidable consequence of living and constitutes the highest risk factor for most human diseases in modern “western” societies. Despise the frequently observed correlation between metabolic alterations and cellular ageing, the molecular mechanisms linking these two complex processes are far from being understood. Here the EpiMetAgeing project proposes to take a novel approach to investigate cell decline linked to obesity and ageing through the lenses of RNA modifications, specifically TET2-mediated 5-hydroxymethylation of cytosines (5hmC). For that purpose, we will characterize the impact of obesity throughout ageing in: (1) the distribution and dynamics of 5hmC epitranscriptomic modification and (2) the key RNA-binding proteins that mediate TET2 function. Given that RNA modifications are reversible, the ultimate goal of this project is to develop novel strategies for cellular rejuvenation. To this end the ER will use cutting-edge technologies, including next-generation sequencing techniques, proteomics, CRISPR activation and repression systems, metabolic phenotyping and iPSC technology. EpiMetAgeing will provide a deeper understanding of the implication of a specific RNA chemical modification in orchestrating metabolism and ageing. Our research has the potential to facilitate the identification of potential druggable targets for therapeutic intervention in age-associated metabolic diseases.
EpiMetAgeing has been carefully designed by combining the ER and host expertise in a highly interdisciplinary research environment to boost her career opportunities, and enhance her possibilities to achieve a position of greater professional maturity and independence that will allow her transition to become a principal investigator in the European R&D system.

Coordinator

UNIVERSIDAD DE SANTIAGO DE COMPOSTELA
Net EU contribution
€ 160 932,48
Address
COLEXIO DE SAN XEROME PRAZA DO OBRADOIRO S/N
15782 Santiago De Compostela
Spain

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Region
Noroeste Galicia A Coruña
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 160 932,48