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 (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciences biological sciences genetics DNA
- natural sciences chemical sciences electrochemistry electrolysis
- medical and health sciences medical biotechnology cells technologies stem cells
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
ERC-2013-CoG
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Host institution
9052 ZWIJNAARDE - GENT
Belgium
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.