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Stress modulates Ahi1-dependent nuclear localization of ten-eleven translocation protein 2.

ABSTRACT: Major depression disorder is one of the most common psychiatric diseases. Recent evidence supports that environmental stress affects gene expression and promotes the pathological process of depression through epigenetic mechanisms. Three ten-eleven translocation (Tet) enzymes are epigenetic regulators of gene expression that promote 5-hydroxymethylcytosine (5hmC) modification of genes. Here, we show that the loss of Tet2 can induce depression-like phenotypes in mice. Paradoxically, using the paradigms of chronic stress, such as chronic mild stress and chronic social defeat stress, we found that depressive behaviors were associated with increased Tet2 expression but decreased global 5hmC level in hippocampus. We examined the genome-wide 5hmC profile in the hippocampus of Tet2 knockout mice and identified 651 dynamically hydroxymethylated regions, some of which overlapped with known depression-associated loci. We further showed that chronic stress could induce the abnormal nuclear translocation of Tet2 protein from cytosol. Through Tet2 immunoprecipitation and mass spectrum analyses, we identified a cellular trafficking protein, Abelson helper integration site-1 (Ahi1), which could interact with Tet2 protein. Ahi1 knockout or knockdown caused the accumulation of Tet2 in cytosol. The reduction of Ahi1 protein under chronic stress explained the abnormal Ahi1-dependent nuclear translocation of Tet2. These findings together provide the evidence for a critical role of modulating Tet2 nuclear translocation in regulating stress response.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC8837822 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Stress modulates Ahi1-dependent nuclear localization of Ten-Eleven Translocation Protein 2

Project description:Three Ten-Eleven Translocation (Tet) enzymes are epigenetic regulators of gene expression that promote 5-hydroxymethylcytosine (5hmC) modification of genes. Here, we show that the loss of Tet2 can induce depression-like phenotypes in mice. Paradoxically, using the paradigms of chronic stress, such as chronic mild stress (CMS) and chronic social defeat stress (CSDS), we found that depressive behaviors were associated with increased Tet2 expression but decreased global 5hmC level in hippocampus. We examined the genome-wide 5hmC profile in the hippocampus of Tet2 knockout mice and identified 651 dynamically hydroxymethylated regions, 31 of which overlapped with known depression-associated loci. We further showed that chronic stress could induce the abnormal nuclear translocation of Tet2 protein from cytosol. Through Tet2 immunoprecipitation and mass spectrum analyses, we identified a cellular trafficking protein, Abelson helper integration site-1 (Ahi1), which could interact with Tet2 protein. Ahi1 knockout or knockdown caused the accumulation of Tet2 in cytosol. The reduction of Ahi1 protein under chronic stress explained the abnormal Ahi1-dependent nuclear translocation of Tet2. These findings together provide the evidence for a critical role of modulating Tet2 nuclear translocation in regulating stress response.

2021-11-22 | GSE167344 | GEO

Stress modulates Ahi1-dependent nuclear localization of Ten-Eleven Translocation Protein 2

Project description:Stress modulates Ahi1-dependent nuclear localization of Ten-Eleven Translocation Protein 2

| PRJNA704360 | ENA

Ten-eleven translocation protein 1 modulates medulloblastoma progression.

Project description:BackgroundMedulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes.ResultsWe investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes.ConclusionsThese results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs.

| S-EPMC8082834 | biostudies-literature

Ten-Eleven Translocation Proteins Modulate the Response to Environmental Stress in Mice.

Project description:5-hydroxymethylcytosine (5hmC) is enriched in brain and has been recognized as an important DNA modification. However, the roles of 5hmC and its writers, ten-eleven translocation (Tet) proteins, in stress-induced response have yet to be elucidated. Here, we show that chronic restraint stress (CRS) induced depression-like behavior in mice and resulted in a 5hmC reduction in prefrontal cortex (PFC). We found that loss of Tet1 (Tet1 KO) led to resistance to CRS, whereas loss of Tet2 (Tet2 KO) increased the susceptibility of mice to CRS. Genome-wide 5hmC profiling identified the phenotype-associated stress-induced dynamically hydroxymethylated loci (PA-SI-DhMLs), which are strongly enriched with hypoxia-induced factor (HIF) binding motifs. We demonstrated the physical interaction between TET1 and HIF1? induced by CRS and revealed that the increased HIF1? binding under CRS is associated with SI-DhMLs. These results suggest that TET1 could regulate stress-induced response by interacting with HIF1?.

| S-EPMC6350936 | biostudies-literature

Ahi1 regulates the nuclear translocation of glucocorticoid receptor to modulate stress response.

Project description:Stress activates the nuclear translocation of glucocorticoid receptors (GR) to trigger gene expression. Abnormal GR levels can alter the stress responses in animals and therapeutic effects of antidepressants. Here, we reported that stress-mediated nuclear translocation of GR reduced Ahi1 in the stressed cells and mouse brains. Ahi1 interacts with GR to stabilize each other in the cytoplasm. Importantly, Ahi1 deficiency promotes the degradation of GR in the cytoplasm and reduced the nuclear translocation of GR in response to stress. Genetic depletion of Ahi1 in mice caused hyposensitivity to antidepressants under the stress condition. These findings suggest that AHI1 is an important regulator of GR level and may serve as a therapeutic target for stress-related disorders.

| S-EPMC8007735 | biostudies-literature

Ten-eleven translocation proteins modulate the response to environmental stress in mice

Project description:5-hydroxymethylcytosine (5hmC) is enriched in brain and has been recognized as an important DNA modification. However, the roles of 5hmC and its “writers”, Ten-eleven translocation (Tet) proteins, in stress-induced response have yet to be elucidated. Here, we show that chronic restraint stress (CRS) induced the depression-like behavior in mice and resulted in a 5hmC reduction in prefrontal cortex (PFC). Interestingly, we found that the loss of Tet1 (Tet1 KO) led to the resistance to CRS while the loss of Tet2 (Tet2 KO) increased the susceptibility of mice to CRS. Genome-wide 5hmC profiling identified the phenotype associated stress-induced dynamically hydroxymethylated loci (PA-SI-DhML), which are strongly enriched with hypoxia-induced factor (HIF) binding motifs. We demonstrated the physical interaction between TET1 and HIF1α induced by CRS, and revealed that the increased HIF1α binding under CRS is associated with SI-DhML. These results together suggest that TET1 could regulate stress-induced response by interacting with HIF1α.

2018-11-21 | GSE106220 | GEO

Multiple Functions of Ten-eleven Translocation 1 during Tumorigenesis.

Project description:ObjectiveAberrant expression of ten-eleven translocation 1 (TET1) plays a critical role in tumor development and progression. We systematically summarized the latest research progress on the role and mechanisms of TET1 in cancer biology.Data sourcesRelevant articles published in English from 1980 to April 2016 were selected from the PubMed database. The terms "ten-eleven translocation 1," "5mC," "5hmC," "microRNA," "hypoxia," and "embryonic stem cell" were used for the search.Study selectionArticles focusing on the role and mechanism of TET1 in tumor were reviewed, including clinical and basic research articles.ResultsTET proteins, the key enzymes converting 5-methylcytosine to 5-hydroxymethylcytosine, play vital roles in DNA demethylation regulation. Recent studies have shown that loss of TET1 is associated with tumorigenesis and can be used as a potential biomarker for cancer therapy, which indicates that TET1 serves as tumor suppressor gene. Moreover, besides its dioxygenase activity, TET1 could induce epithelial-mesenchymal transition and act as a coactivator to regulate gene transcription, such as developmental regulator in embryonic stem cells (ESCs) and hypoxia-responsive gene in cancer. The regulation of TET1 is also correlated with microRNA in a posttranscriptional modification process. Hence, it is complex but critical to comprehend the mechanisms of TET1 in the biology of ESCs and cancer.ConclusionsTET1 not only serves as a demethylation enzyme but also plays multiple roles during tumorigenesis and progression. More studies should be carried out to elucidate the exact mechanisms of TET1 and its associations with cancer before considering it as a therapeutic tool.

| S-EPMC4960967 | biostudies-literature

5-Hydroxymethylcytosine and ten-eleven translocation dioxygenases in head and neck carcinoma.

Project description:Ten-eleven translocation (TET) enzymes are implicated in DNA demethylation through dioxygenase activity, which converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC). However, the specific roles of TET enzymes and 5-hmC levels in head and neck squamous cell carcinoma (HNSCC) have not yet been evaluated. In this study, we analyzed 5-hmC levels and TET mRNA expression in a well-characterized dataset of 117 matched pairs of HNSCC tissues and normal tissues. 5-hmC levels and TET mRNA expression were examined via enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. 5-hmC levels were evaluated according to various clinical characteristics and prognostic implications. Notably, we found that 5-hmC levels were significantly correlated with tumor stage (P = 0.032) and recurrence (P = 0.018). Univariate analysis revealed that low levels of 5-hmC were correlated with poor disease-free survival (DFS; log-rank test, P = 0.038). The expression of TET family genes was not associated with outcomes. In multivariate analysis, low levels of 5-hmC were evaluated as a significant independent prognostic factor of DFS (hazard ratio: 2.352, 95% confidence interval: 1.136-4.896; P = 0.021). Taken together, our findings showed that reduction of TET family gene expression and subsequent low levels of 5-hmC may affect the development of HNSCC.

| S-EPMC6775623 | biostudies-literature

L1 retrotransposition is activated by Ten-eleven-translocation protein 1 and repressed by methyl-CpG binding proteins.

Project description:One of the major functions of DNA methylation is the repression of transposable elements, such as the long-interspersed nuclear element 1 (L1). The underlying mechanism(s), however, are unclear. Here, we addressed how retrotransposon activation and mobilization are regulated by methyl-cytosine modifying ten-eleven-translocation (Tet) proteins and how this is modulated by methyl-CpG binding domain (MBD) proteins. We show that Tet1 activates both, endogenous and engineered L1 retrotransposons. Furthermore, we found that Mecp2 and Mbd2 repress Tet1-mediated activation of L1 by preventing 5hmC formation at the L1 promoter. Finally, we demonstrate that the methyl-CpG binding domain, as well as the adjacent non-sequence specific DNA binding domain of Mecp2 are each sufficient to mediate repression of Tet1-induced L1 mobilization. Our study reveals a mechanism how L1 elements get activated in the absence of Mecp2 and suggests that Tet1 may contribute to Mecp2/Mbd2-deficiency phenotypes, such as the Rett syndrome. We propose that the balance between methylation "reader" and "eraser/writer" controls L1 retrotransposition.

| S-EPMC5703239 | biostudies-literature

Ten-eleven translocation 2 interacts with forkhead box O3 and regulates adult neurogenesis.

Project description:Emerging evidence suggests that active DNA demethylation machinery plays important epigenetic roles in mammalian adult neurogenesis; however, the precise molecular mechanisms and critical functional players of DNA demethylation in this process remain largely unexplored. Ten-eleven translocation (Tet) proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and its downstream derivatives. Here we show that 5hmC is elevated during the differentiation of adult neural stem cells (aNSCs), and Tet2 is primarily responsible for modulating 5hmC dynamics. Depletion of Tet2 leads to increased aNSC proliferation and reduced differentiation in vitro and in vivo. Genome-wide transcriptional analyses reveal important epigenetic roles of Tet2 in maintaining the transcriptome landscape related to neurogenesis. Mechanistically, transcription factor forkhead box O3 (Foxo3a) physically interacts with Tet2 and regulates the expression of genes related to aNSC proliferation. These data together establish an important role for the Tet2-Foxo3a axis in epigenetically regulating critical genes in aNSCs during adult neurogenesis.

| S-EPMC5493768 | biostudies-literature

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