Objective DNA methylation was originally described in the 1970s as an epigenetic mark involved in transcriptional silencing, but the existence of DNA demethylation and the enzymes involved in this process were only recently discovered. In particular, it was established that TET hydroxylases catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) through a reaction requiring oxygen (O2) and 2-oxoglutarate (2OG). DNA demethylation as mediated by TET hydroxylases has so far predominantly been studied in the context of stem cells, but its precise contribution to carcinogenesis remains largely enigmatic. Nevertheless, somatic mutations in TETs have been identified in numerous cancers.Tumor hypoxia is linked to increased malignancy, poor prognosis and resistance to cancer therapies. In this proposal, we aim to assess how hypoxia directly impacts on the cancer epigenome through the dependence of TET-mediated DNA demethylation on O2. First of all, we will study the effect of O2 and 2OG concentration on TET hydroxylase activity, as well as the overall and locus-specific changes of their product (5hmC). Secondly, because much of the hypoxic response is executed through HIFs, we will investigate how HIF binding is influenced by DNA methylation and if so, whether TET hydroxylases are targeted to HIF (or other) binding sites to maintain them transcriptionally active. Thirdly, we will assess to what extent 5hmC profiles differ between tumor types and construct a comprehensive panel of (tumor-specific) 5hmC sites to assess the global and locus-specific relevance of 5hmC in various cancers. Finally, since hypoxia is a key regulator of the cancer stem cell (CSC) niche and within the tumor microenvironment also promotes metastasis, we will establish the in vivo relevance of DNA demethylation, as imposed by tumor hypoxia, in the CSC niche and during metastasis. Overall, we thus aim to establish the interplay between tumor hypoxia and the DNA methylome. Fields of science natural sciencesbiological sciencesgeneticsDNAnatural scienceschemical scienceselectrochemistryelectrolysismedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-CG-2013-LS2 - ERC Consolidator Grant - Genetics, Genomics, Bioinformatics and Systems Biology Call for proposal ERC-2013-CoG See other projects for this call Funding Scheme ERC-CG - ERC Consolidator Grants Host institution VIB VZW EU contribution € 1 920 000,00 Address SUZANNE TASSIERSTRAAT 1 9052 ZWIJNAARDE - GENT Belgium See on map Region Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent Activity type Research Organisations Administrative Contact Rik Audenaert (Mr.) Principal investigator Diether Lambrechts (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all VIB VZW Belgium EU contribution € 1 920 000,00 Address SUZANNE TASSIERSTRAAT 1 9052 ZWIJNAARDE - GENT See on map Region Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent Activity type Research Organisations Administrative Contact Rik Audenaert (Mr.) Principal investigator Diether Lambrechts (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data