TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA526452 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8707460_1.fastq.gz | Fastqsanger.gz | |||
| SRR8707460_2.fastq.gz | Fastqsanger.gz | |||
| SRR8707457_1.fastq.gz | Fastqsanger.gz | |||
| SRR8707457_2.fastq.gz | Fastqsanger.gz | |||
| SRR8707458_1.fastq.gz | Fastqsanger.gz |
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Project description:Ten-eleven translocation methylcytosine dioxygenase-1, TET1, takes part in active DNA demethylation. This study showed that TET1 expression reprogramed ovarian cancer epigenome and correlated with poor survival in advanced-stage epithelial ovarian carcinoma (EOC).
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Project description:Ten-eleven translocation methylcytosine dioxygenase-1, TET1, takes part in active DNA demethylation. However, our understanding of DNA demethylation in cancer biology and its clinical significance remain limited. This study showed that TET1 expression correlated with poor survival in advanced-stage epithelial ovarian carcinoma (EOC), and with cell migration, anchorage-independent growth, cancer stemness, and tumorigenicity. In particular, TET1 was highly expressed in serous tubal intraepithelial carcinoma (STIC), a currently accepted type II EOC precursor, and inversely correlated with TP53 mutations. Moreover, TET1 could demethylate the epigenome and activate multiple oncogenic pathways, including an immunomodulation network having casein kinase II subunit alpha (CK2α) as a hub. Patients with TET1high CK2αhigh EOCs had the worst outcomes, and TET1-expressing EOCs were more sensitive to a CK2 inhibitor, both in vitro and in vivo. Our findings uncover the oncogenic and poor prognostic roles of TET1 in EOC and suggest an unexplored role of epigenetic reprogramming in early ovarian carcinogenesis. Moreover, the immunomodulator CK2α represents a promising new therapeutic target, warranting clinical trials of the tolerable CK2 inhibitor, CX4945, for precision medicine against EOC. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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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.
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Project description:The segregation of maternal centromeres away from the paternal ones during the first division of meiosis depends on the attachment of sister kinetochores to microtubules emanating from the same spindle pole. In budding yeast monopolar attachment requires the recruitment to kinetochores of a protein complex called monopolin. The biochemical function of monopolin was unknown. Here, we have identified the casein kinase I Hrr25 as a hitherto unknown subunit of monopolin. Hrr25 differs from other monopolin components by its enzymatic activity and strong evolutionary conservation. We demonstrate that Hrr25’s kinase activity and its interaction with monopolin are both required for monopolar attachment. Accordingly, Hrr25 is associated with centromeres in meiosis I. Our results revealed a surprising new role for casein kinases and provide a hypothesis for the mechanism of monopolar attachment during meiosis I in sexually reproducing organisms: casein kinase I-dependent phosphorylation of kinetochore proteins. Keywords: ChIP-chip, Meiosis, Cell cycle, Saccharomyces cerevisiae, Chromosome VI tiling array, Hrr25, Mam1
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Project description:Precise regulation of DNA methylation in mammals is critical for genome stability and epigenetic regulation. The discovery of the ten-eleven translocation (TET) proteins catalyzing the oxidation from 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) revolutionized the perspective on the complexity and regulation of DNA modifications. Despite accumulating knowledge about the role of TET1, it remains unclear to what extent these can be attributed to its catalytic activity. Here, we use genome engineering and quantitative multi-omics approaches to dissect the role and mechanism of TET1 in mESCs. Our study identifies TET1 as an essential interaction hub for multiple chromatin modifying complexes and as a global regulator of histone modifications. Strikingly, we find that the majority of transcriptional regulation depends on non-catalytic functions of TET1. Moreover, we show that the establishment of H3K9me3 and H4K20me3 at ERV1, ERVK, and ERVL is mediated by TET1 independent of DNA demethylation. We provide evidence that repression of endogenous retroviruses depends on the interaction between TET1 and SIN3A. In summary, we demonstrate that the non-catalytic functions of TET1 are critical for regulation of gene expression and the silencing of endogenous retroviruses in mESCs.
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Project description:Nur77 is a member of the NR4A subfamily of nuclear receptors and has been shown to regulate various biological processes such as apoptosis and inflammation. Here, we show that Nur77 ubiquitination is mediated by the tripartite motif 13 (Trim13), a RING-type E3 ubiquitin ligase. The interaction between Nur77 and Trim13 was confirmed by co-immunoprecipitation. Moreover, we found that Lys539 in Nur77 ubiquitination is targeted for Trim13, which leads to Nur77 degradation. The Trim13-mediated ubiquitination of Nur77 was optimal in the presence of the E2 enzyme UbcH5. Importantly, in addition to Trim13-mediated ubiquitination, the stability of Nur77 was also regulated by casein kinase 2α (CK2α). Pharmacological inhibition of CK2 markedly increased Nur77 levels, whereas overexpression of CK2α, but not its inactive mutant, dramatically decreased Nur77 levels by promoting Nur77 ubiquitination. CK2α phosphorylated Ser154 in Nur77 and thereby regulated Nur77 protein levels by promoting its ubiquitin-mediated degradation. Importantly, we also show that degradation of Nur77 is involved in TNFα-mediated IL-6 production via CK2α and Trim13. Taken together, these results suggest that the sequential phosphorylation and ubiquitination of Nur77 controls its degradation, and provide a therapeutic approach for regulating Nur77 activity through the CK2α-Trim13 axis as a mechanism to control the inflammatory response.
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Project description:Mutational inactivation of VHL is the earliest genetic event in the majority of ccRCCs, leading to activation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCCs and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Using an autochthonous ccRCC model, we show genetically that Hif1a is necessary for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are necessary for the clear cell phenotype. Transcriptomic and proteomic analyses revealed that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. Deficiency of HIF-2α increased CD8+ T cell infiltration and activation. These studies reveal different functions of HIF-1α and HIF-2α in ccRCC. SIGNIFICANCE The roles of HIF-1α and HIF-2α in ccRCC pathogenesis remain unclear. Using a mouse genetic approach we show that HIF-1α but not HIF-2α is important for tumour formation, contrary to predictions from studies of human ccRCC. We show that HIF-1α and HIF-2α transcriptionally regulate different aspects of metabolism and identify HIF-2α as a suppressor of immune cell infiltration and activation.
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