TET1 regulates hypoxia-induced epithelial-mesenchymal transition through DNA demethylation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE59990 | GEO | 2014/08/01
SECONDARY ACCESSION(S): PRJNA257214
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-08-01 | E-GEOD-59990 | biostudies-arrayexpress
Project description:In order to explore the status of DNA methylation in hypoxia response, we show that TET1, a DNA dioxygenase converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates hypoxia-responsive gene expression. Hypoxia/HIF-2α regulates the expression of TET1. Knockdown of TET1 mitigated hypoxia-induced EMT. RNA sequencing and 5hmC sequencing identified the set of TET1-regulated genes. Four samples (Four samples, Hypoxia (scrambled control), Hypoxia (TET1-si), Normoxia (scrambled control) and Normoxia (TET1-si), are performed by RNA-Seq and hMeDIP-Seq
2014-08-01 | E-GEOD-59989 | biostudies-arrayexpress
Project description:In order to explore the status of DNA methylation in hypoxia response, we show that TET1, a DNA dioxygenase converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates hypoxia-responsive gene expression. Hypoxia/HIF-2α regulates the expression of TET1. Knockdown of TET1 mitigated hypoxia-induced EMT. RNA sequencing and 5hmC sequencing identified the set of TET1-regulated genes. Four samples (Four samples, Hypoxia (scrambled control), Hypoxia (TET1-si), Normoxia (scrambled control) and Normoxia (TET1-si), are performed by RNA-Seq and hMeDIP-Seq RNA-Seq and hMeDIP-Seq
2014-08-01 | E-GEOD-59987 | biostudies-arrayexpress
Project description:In order to explore the status of DNA methylation in hypoxia response, we show that TET1, a DNA dioxygenase converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates hypoxia-responsive gene expression. Hypoxia/HIF-2α regulates the expression of TET1. Knockdown of TET1 mitigated hypoxia-induced EMT. RNA sequencing and 5hmC sequencing identified the set of TET1-regulated genes.
2014-08-01 | GSE59989 | GEO
Project description:In order to explore the status of DNA methylation in hypoxia response, we show that TET1, a DNA dioxygenase converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates hypoxia-responsive gene expression. Hypoxia/HIF-2α regulates the expression of TET1. Knockdown of TET1 mitigated hypoxia-induced EMT. RNA sequencing and 5hmC sequencing identified the set of TET1-regulated genes.
2014-08-01 | GSE59987 | GEO
Project description: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.We show that TET1 regulates hypoxia-responsive gene expression. Hypoxia/HIF-2? 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? and HIF-2? 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?. We define the domain in HIF-1? 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.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.
| S-EPMC4253621 | biostudies-literature
Project description:IntroductionAdenylyl cyclase isoform 6 (ADCY6) is a member of membrane-bound adenylate cyclase family that converts adenosine triphosphate (ATP) into cAMP and pyrophosphate. An increasing number of researchers have studied the role of ADCY6 in cancer. However, its specific role in breast cancer remains unknown.MethodsBioinformatics and clinical data were used to analyse the expression of ADCY6 in breast cancer. ADCY6 DNA methylation was analysed using DNA methylation-specific PCR and Bisulfite Sanger sequencing. Using lentiviral stable miRNA transfection together with cell biology functional assays and gene expression/target analysis, we investigated the interaction between miR-27a-3p, TET1 and ADCY6 in breast cancer.ResultsWe found that ADCY6 is expressed at low levels in breast cancer and leads to increases in the proliferation, invasion and migration of breast cancer cells. The low expression of ADCY6 is due to the lower demethylation of ten-eleven translocation methylcytosine dioxygenase 1 (TET1), and the methylation of ADCY6 can be altered by TET1. More importantly, bioinformatics analysis showed that TET1 is regulated by miR-27a-3p and regulates the methylation of ADCY6 to affect the EMT process of breast cancer cells, thereby affecting the malignant biological behaviour of breast cancer.ConclusionsOur study demonstrates that the methylation modification of ADCY6 is regulated by TET1 and leads to ADCY6 activation. miR-27a-3p negatively regulates the expression of TET1 and affects the EMT process of breast cancer through ADCY6, thereby promoting the malignant biological behaviour of breast cancer. Our results may provide new research ideas and directions for DNA methylation and EMT changes in breast cancer.
| S-EPMC9377375 | biostudies-literature
Project description:BackgroundEndometriosis (EMs) is a non-malignant gynecological disease, whose pathogenesis remains to be clarified. Recent studies have found that hypoxia induces epithelial-mesenchymal transition (EMT) as well as epigenetic modification in EMs. However, the relationship between EMT and demethylation modification under hypoxia status in EMs remains unknown.MethodsThe expression of N-cadherin, E-cadherin and TET1 in normal endometria, eutopic endometria and ovarian endometriomas was assessed by immunohistochemistry and immunofluorescence double staining. 5-hmC was detected by fluorescence-based ELISA kit using a specific 5-hmC antibody. Overexpression and inhibition of TET1 or hypoxia-inducible factor 2α (HIF-2α) were performed by plasmid and siRNA transfection. The expression of HIF-2α, TET1 and EMT markers in Ishikawa (ISK) cells (widely used as endometrial epithelial cells) was evaluated by western blotting. The interaction of HIF-2α and TET1 was analyzed by chromatin immunoprecipitation.ResultsDemethylation enzyme TET1 (ten-eleven translocation1) was elevated in glandular epithelium of ovarian endometrioma, along with the activation of EMT (increased expression of N-cadherin, and decreased expression of E-cadherin) and global increase of epigenetic modification marker 5-hmC(5-hydroxymethylcytosine). Besides, endometriosis lesions had more TET1 and N-cadherin co-localized cells. Further study showed that ISK cells exhibited enhanced EMT, and increased expression of TET1 and HIF-2α under hypoxic condition. Hypoxia-induced EMT was partly regulated by TET1 and HIF-2α. HIF-2α inhibition mitigated TET1 expression changes provoked by hypoxia.ConclusionsHypoxia induces the expression of TET1 regulated by HIF-2α, thus may promote EMT in endometriosis.
| S-EPMC7500323 | biostudies-literature
Project description:Epigenetic regulations including DNA methylation and demethylation play critical roles in neural development. However, whether DNA methylation and demethylation may play a role in neuronal cell death remains largely unclear. Here we report that the blockade of DNA methyltransferase inhibits apoptosis of cerebellar granule cells and cortical neurons in response to oxidative stress. We found that knockdown of ten-eleven translocation methylcytosine dioxygenase (Tet1), a critical enzyme for DNA demethylation, significantly increase apoptosis of cerebellar granule cells induced by hydrogen peroxide. Moreover, cerebellar granule cells from tet1(null) mice appeared to be more sensitive to oxidative stress, suggesting the critical role of Tet1 in neuronal cell death. We further showed that the expression of Klotho, an antiaging protein, in cerebellar granule cells is tightly regulated by DNA methylation. Finally, we found that knockdown of Klotho diminished the rescue effects of DNA methyltransferase inhibitors and Tet1 on neuronal cell death induced by oxidative stress. Our work revealed the role of Tet1-mediated DNA demethylation on neuronal protection against oxidative stress and provided the molecular mechanisms underlying the epigenetic regulation of neuronal cell death, suggesting the role of Klotho in regulating neuronal cell death in response to oxidative stress.
| S-EPMC4284502 | biostudies-literature
Project description:Hypoxia is regarded as one of the pathophysiologic mechanisms of kidney injury and further progression to kidney failure. Epithelial-to-mesenchymal transition (EMT) in kidney tubules is a critical process of kidney fibrosis. This study utilized transcriptome analysis to investigate hypoxia-induced EMT through microRNA (miRNA)-modulated EMT in proximal tubular epithelial cells (PTECs). RNA sequencing revealed eight miRNAs were upregulated and three miRNAs were downregulated in PTECs cultured under hypoxia compared with normoxia. Among the 11 miRNAs, miR-545-3p has the highest expression in PTECs exposed to hypoxia, and miR-545-3p suppressed tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/TNFSF10) expression. Hypoxia induced EMT in PTECs through miR-545-3p-TNFSF10 modulation, and TNFSF10-attenuated EMT resulted from hypoxia or miR-545-3p mimic transfection. These findings provided new perceptions of the unique regulation of the miR-545-3p-TNFSF10 interaction and their potential therapeutic effect in kidney injury induced by hypoxia.
| S-EPMC8301867 | biostudies-literature