TET1 regulates hypoxia-induced epithelial-mesenchymal transition by acting as a co-activator

Abstract

BackgroundHypoxia 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.ResultsWe show that TET1 regulates hypoxia-responsive gene expression. Hypoxia/HIF-2α 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-1α and HIF-2α 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-2α. We define the domain in HIF-1α 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0513-0) contains supplementary material, which is available to authorized users.

Tet1 and Tet2 Protect DNA Methylation Canyons against Hypermethylation

“…Hypermethylation can therefore have context-dependent effects on gene expression, leading to up-or downregulation of canyon-associated genes (see Table S3 in the supplemental material). In addition, especially for Tet1, gene-regulatory functions (repressive and activating) independent of its enzymatic activity have been described (41,42). This might in part account for Tet-dependent effects on gene expression that are apparently not correlated with hypermethylation.…”

Differential expression of ten-eleven translocation genes in endometrial cancers

“…TET1 also interacts with the SIN3A co-repressor complex leading to transcriptional repression of many TET1-targeted genes. [29][30][31] TET2 and TET3 can interact with O-GlcNAc transferase (OGT), and these interactions promote GlcNAcylation and increase H3K4me3 through the SET1/ COMPASS complex. 32 Non-catalytic activities of TETs cause that except tumor-suppressing function they also have tumor-promoting function.…”

Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

“…TET hydroxylates 5-methylcytosine to generate 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxycytosine in the consecutive biochemical reactions [85]. It has been reported that TET1 functions as a HIF coactivator and controls HIF-1-dependent epithelial-mesenchymal transition in breast cancer cells [86]. The protein interaction of TET1 with HIF-1α and HIF-2α, but not its DNA demethylase activity, is critical for HIF activation.…”