Journal
GENOME BIOLOGY
Volume 15, Issue 12, Pages -Publisher
BMC
DOI: 10.1186/s13059-014-0513-0
Keywords
-
Funding
- Ministry of Science and Technology Summit grant [MOST 103-2745-B-039-001-ASP]
- National Science Council Frontier grant [NSC102-2321-B-010-001]
- National Research Program for Biopharmaceuticals [NSC102-2325-B-010-004]
- Ministry of Education, Aim for the Top University Plan [103 AC-T301]
- center of excellence for cancer research at Taipei Veterans General Hospital [MOHW103-TD-B-111-02]
- Taichung Veterans General Hospital [TCVGH-YM1010301]
- Kee-Lung Chang-Gung Memorial Hospital [CMRPG2D0031]
- National Health Research Institutes [NHRI-EX102-10230SI, NHRI-EX103-10230SI]
Ask authors/readers for more resources
Background: Hypoxia induces the epithelial-mesenchymal transition, EMT, to promote cancer metastasis. In addition to transcriptional regulation mediated by hypoxia-inducible factors, HIFs, other epigenetic mechanisms of gene regulation, such as histone modifications and DNA methylation, are utilized under hypoxia. However, whether DNA demethylation mediated by TET1, a DNA dioxygenase converting 5-methylcytosine, 5mC, into 5-hydroxymethylcytosine, 5hmC, plays a role in hypoxia-induced EMT is largely unknown. Results: We show that TET1 regulates hypoxia-responsive gene expression. Hypoxia/HIF-2 alpha regulates the expression of TET1. Knockdown of TET1 mitigates hypoxia-induced EMT. RNA sequencing and 5hmC sequencing identified the set of TET1-regulated genes. Cholesterol metabolic process genes are among the genes that showed high prevalence and statistical significance. We characterize one of the genes, INSIG1 (insulin induced gene 1), to confirm its expression and the 5hmC levels in its promoter. Knockdown of INSIG1 also mitigates hypoxia-induced EMT. Finally, TET1 is shown to be a transcriptional co-activator that interacts with HIF-1 alpha and HIF-2 alpha to enhance their transactivation activity independent of its enzymatic activity. TET1 acts as a co-activator to further enhance the expression of INSIG1 together with HIF-2 alpha. We define the domain in HIF-1 alpha a that interacts with TET1 and map the domain in TET1 that confers transactivation to a 200 amino acid region that contains a CXXC domain. The TET1 catalytically inactive mutant is capable of rescuing hypoxia-induced EMT in TET1 knockdown cells. Conclusions: These findings demonstrate that TET1 serves as a transcription co-activator to regulate hypoxia-responsive gene expression and EMT, in addition to its role in demethylating 5mC.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available