CHAMELEO · Cellular Hypoxia Alters DNA Methylation through Loss of Epigenome Oxidation
FP7 — People (Marie Curie Actions)
- Duration
- 2013-05-01 → 2016-04-30
- EU contribution
- €75,000
- Participants
- 1
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
Cellular Hypoxia Alters DNA Methylation through Loss of Epigenome Oxidation
Hypermethylation of tumor suppressor gene (TSG) promoters confers growth advantages to cancer cells, but how these changes arise is poorly understood. We demonstrate that tumor hypoxia reduces the activity of oxygen-dependent TET enzymes, which catalyze DNA de-methylation through 5-methylcytosine oxidation. This occurs independently of hypoxia-associated alterations in TET gene expression, basal metabolism, HIF activity or nuclear reactive oxygen species, but directly depends on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro. Also in patients, gene promoters are markedly more methylated in hypoxic than normoxic tumors. Affected genes are frequently involved in DNA repair, cell cycle regulation, angiogenesis and metastasis, indicating cellular selection of hypermethylation events. Overall, up to 50% of the tumor-associated hypermethylation is ascribable to hypoxia across various cancer types. Accordingly, spontaneous murine breast tumors become hypermethylated when rendered hypoxic through vessel pruning, whereas vessel normalisation rescues this effect. Tumor hypoxia thus acts as a novel regulator underlying DNA methylation.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- VIB VZW · ZWIJNAARDE - GENTCoordinatorBelgium
Links
Data: CORDIS, © European Union