Objective Post-translational chemical modifications to histone proteins – the storage units of DNA – influence gene expression electrostatically and through specific protein-protein interactions, the study of which is known as epigenetics. Although many enzymes have been identified which add, remove or recognise these modifications, the implication of metabolism in the induction of epigenetic states is a recent development – particularly highlighting acetyl coenzyme A (CoA) as the sole donor for acetylation. Due to the lack of appropriate biochemical tools, this emerging field has not yet been exploited, however Acies Bio’s leading work on the efficient synthesis of 4’ phosphopantetheine (4-PPT), a natural precursor of the prolific substrate CoA, places us in a unique position to realise the novel approach of metabolically inducing epigenetic modifications. In progress towards therapeutic use bypassing faulty metabolism in a rare genetic disorder, we have shown that 4-PPT is cell permeable, serum-stable, tolerated at high doses without side-effects, and can also upregulate histone acetylation. This presents a previously unexplored route to develop 4-PPT as a novel vehicle for the delivery of diverse intracellular acyl-CoA species, and subsequent histone modification. Taking advantage of the interplay between metabolic and epigenetic states, and the complementarity of backgrounds that Acies Bio and Dr Sekirnik can provide through an international partnership combining expertise in both fields, our proposed work would illuminate recently characterised histone acylations. By synthesising novel 4-PPT derivatives, and demonstrating their activity on a cellular and model organism level, we will develop new tools to enable rapid enrichment of rare endogenous modifications to probe their function. This would form the first demonstration of use of native enzyme substrates to affect epigenetic states, affording new European research opportunities in both metabolomics and epigenetics. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsnatural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymesnatural sciencesbiological sciencesgeneticsepigenetics Keywords chemical biology tools metabolic induction enriching natural epigentic modification 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-2016 - Individual Fellowships Call for proposal H2020-MSCA-IF-2016 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator ACIES BIO BIOTEHNOLOSKE RAZISKAVE IN RAZVOJ DOO Net EU contribution € 157 287,60 Address Tehnoloski park 21 1000 Ljubljana Slovenia See on map Region Slovenija Zahodna Slovenija Osrednjeslovenska Activity type Private for-profit entities (excluding 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 Other funding € 0,00
