CHAMELEO

Cellular Hypoxia Alters DNA Methylation through Loss of Epigenome Oxidation

Coordinatore	VIB    more  Organization address address: Rijvisschestraat 120 city: ZWIJNAARDE - GENT postcode: 9052 contact info Titolo: Mr. Nome: Rik Cognome: Audenaert Email: send email Telefono: 3292446611 Fax: 3292446610
Nazionalità Coordinatore	Belgium [BE]
Totale costo	75˙000 €
EC contributo	75˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2012-CIG
Funding Scheme	MC-CIG
Anno di inizio	2013
Periodo (anno-mese-giorno)	2013-05-01   -   2016-04-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	VIB  Organization address address: Rijvisschestraat 120 city: ZWIJNAARDE - GENT postcode: 9052 contact info Titolo: Mr. Nome: Rik Cognome: Audenaert Email: send email Telefono: 3292446611 Fax: 3292446610	BE (ZWIJNAARDE - GENT)	coordinator	75˙000.00

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 Obiettivo del progetto (Objective)

'DNA methylation is integral to the regulation of gene transcription but is deregulated in cancer. Mechanisms causing this dysregulation are however poorly understood. Although DNA methylation mechanisms were described for several decades ago, the enzymes responsible for DNA demethylation were only discovered a few years ago: TET enzymes catalyze the conversion of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) through a reaction requiring oxygen and 2-oxoglutarate (2OG). Interestingly, decreased oxygen concentrations (hypoxia) are common in cancer, as is an altered 2OG metabolism. Hypoxia induces the activity of Hypoxia Inducible Factor (HIF) transcription factors, which alter gene expression in cells to counter and cope with hypoxia. It is however poorly characterized how DNA methylation influences HIF binding, and how HIF in turn interfaces with the epigenome.

In CHAMELEO, we aim to investigate the influence of hypoxia on the epigenome and the resulting phenotypic response in cancer. Firstly, we hypothesize that promoters of tumor suppressor gene can be hypermethylated through inhibition of DNA demethylation at low oxygen concentrations, thus contributing to oncogenic transformation. To investigate this, we will study the dependence of TET DNA hydroxylases on oxygen and 2OG, as well as the overall and locus-specific changes upon hypoxia 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 how HIFs interface with epigenetic modulators such as TETs. Experiments in vitro and in vivo will be combined with state-of-the-art high-throughput sequencing techniques, and are expected to provide an unambiguous and comprehensive view on the role of DNA methylation dynamics in hypoxia and cancer.'