Objective Epigenetics research has revealed that in the cell’s nucleus all kinds of biomolecules–DNA, RNAs, proteins, protein posttranslational modifications–are highly compartmentalized to occupy distinct chromatin territories and genomic loci, thereby contributing to gene regulation and cell identity. In contrast, small molecules and cellular metabolites are generally considered to passively enter the nucleus from the cytoplasm and to lack distinct subnuclear localization. The CHROMABOLISM proposal challenges this assumption based on preliminary data generated in my laboratory. I hypothesize that chromatin-bound enzymes of central metabolism and subnuclear metabolite gradients contribute to gene regulation and cellular identity.To address this hypothesis, we will first systematically profile chromatin-bound metabolic enzymes, chart nuclear metabolomes across representative leukemia cell lines, and develop tools to measure local metabolite concentrations at distinct genomic loci. In a second step, we will then develop and apply technology to perturb these nuclear metabolite patterns by forcing the export of metabolic enzymes for the nucleus, aberrantly recruiting these enzymes to selected genomic loci, and perturbing metabolite patterns by addition and depletion of metabolites. In all these conditions we will measure the impact of nuclear metabolism on chromatin structure and gene expression. Based on the data obtained, we will model for the effects of cellular metabolites on cancer cell identity and proliferation. In line with the recent discovery of oncometabolites and the clinical use of antimetabolites, we expect to predict chromatin-bound metabolic enzymes that can be exploited as druggable targets in oncology. In a final aim we will validate these targets in leukemia and develop chemical probes against them.Successful completion of this project has the potential to transform our understanding of nuclear metabolism in control of gene expression and cellular identity. Fields of science natural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesgeneticsRNAmedical and health sciencesclinical medicineoncologyleukemianatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymesnatural sciencesbiological sciencesgeneticsepigenetics Keywords folate metabolism nuclear metabolomics transcription target discovery Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2017-COG - ERC Consolidator Grant Call for proposal ERC-2017-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH Net EU contribution € 1 980 916,00 Address LAZARETTGASSE 14 AKH BT 25.3 1090 Wien Austria See on map Region Ostösterreich Wien Wien 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 Total cost € 1 980 916,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH Austria Net EU contribution € 1 980 916,00 Address LAZARETTGASSE 14 AKH BT 25.3 1090 Wien See on map Region Ostösterreich Wien Wien 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 Total cost € 1 980 916,00
