TET2 regulates osteoclast differentiation by interacting with RUNX1 and maintaining genomic 5-hydroxymethylcytosine
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE104828 | GEO | 2018/05/01
REPOSITORIES: GEO
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Project description:As a dioxygenase, Ten-Eleven Translocation 2 (TET2) catalyzes subsequent steps of 5-methylcytosine (5mC) oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hematopoietic stem cells, but its impact on mature hematopoietic cells is not well-characterized. Here we show that Tet2 plays an essential role in osteoclastogenesis. Deletion of Tet2 impairs the differentiation of osteoclast precursor cells (macrophages) and their maturation into bone-resorbing osteoclasts in vitro. Furthermore, Tet2-/- mice exhibit mild osteopetrosis, accompanied by decreased number of osteoclasts in vivo. Tet2 loss in macrophages results in the altered expression of a set of genes implicated in osteoclast differentiation, such as Cebpa, Mafb, and Nfkbiz. Tet2 deletion also leads to a genome-wide alteration in the level of 5-hydroxymethylcytosine (5hmC) and altered expression of a specific subset of macrophage genes associated with osteoclast differentiation. Furthermore, Tet2 interacts with Runx1 and negatively modulates its transcriptional activity. Our studies demonstrate a novel molecular mechanism controlling osteoclast differentiation and function by Tet2, that is, through interactions with Runx1 and the maintenance of genomic 5hmC. Targeting Tet2 and its pathway could be a potential therapeutic strategy for the prevention and treatment of abnormal bone mass caused by the deregulation of osteoclast activities.
| S-EPMC6076382 | biostudies-literature
Project description:TET2 regulates osteoclast differentiation by interacting with RUNX1 and maintaining genomic 5-hydroxymethylcytosine
| PRJNA413945 | ENA
Project description:Ten eleven translocation 2 (TET2) is a member of dioxygenases that catalyze the multi-step 5-methylcytosine oxidation. Loss-of-function TET2 mutations frequently occur in various types of hematological malignancies; however, the underlying mechanism remains poorly understood. Here, we show that Tet2-/- mice develop spontaneous myeloid, T- and B-cell malignancies. Exome sequencing of Tet2-/- tumors reveals acquisition of numerous mutations. The mutational frequency in Tet2-/- tumors is significantly greater at loci containing Tet2-dependent active demethylation sites. In addition, the analyses of TET2-interacting protein unveil the association between TET2 and MutS Homolog 6 (MSH6). TET2-depleted cells display elevated spontaneous mutational frequencies and increased microsatellite instability, characteristics of mismatch repair deficient cells. Furthermore, myelodysplastic syndrome (MDS) patients with mutant TET2 have significantly higher mutational events than patients with wild-type TET2. Our findings reveal genomic hypermutability driven by the loss of TET2 as a novel contributing mechanism for TET2 loss-mediated pathogenesis of diverse hematological malignancies.
2017-04-25 | GSE74390 | GEO
Project description:Ten-Eleven-Translocation-2 (Tet2) is a DNA methylcytosine dioxygenase that functions as a tumor suppressor in hematopoietic malignancies. In this study, we revealed a role for Tet2 in sustaining the immunosuppressive function of tumor-tissue myeloid cells. We found that Tet2 expression is increased in intratumoral myeloid cells both in mouse models of melanoma and in melanoma patients, and that this increased expression is dependent on an IL-1R-MyD88 pathway. Ablation of Tet2 in myeloid cells suppressed melanoma growth in vivo, and shifted the immunosuppressive gene expression program in tumor-associated macrophages to a proinflammatory one, with a concomitant reduction of the immunosuppressive function. This resulted in increased numbers of effector T cells in the tumor, and T cell depletion abolished the reduced tumor growth observed upon myeloid-specific deletion of Tet2. Our findings reveal a non-cell-intrinsic, tumor-promoting function for Tet2, and suggest that Tet2 may present a therapeutic target for the treatment of non-hematologic malignancies.
2017-08-15 | GSE98964 | GEO
Project description:Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes implicated in cancer and in aging due to its role as a global epigenetic modifier. TET2 has a large N-terminal domain followed by a catalytic C-terminal. Previous reports have demonstrated that the catalytic domain remains active independent of the N-terminal domain. As such, the function of the N-terminus of this large protein remains poorly characterized. Here, we identify that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3s bind TET2 when phosphorylated at serine 99 (S99). AMPK-mediated phosphorylation at S99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine. 14-3-3s’ interaction with TET2 serves to protect S99 phosphorylation. Disruption of this interaction leads to both reduced TET2 phosphorylation and decreased protein stability. Furthermore, we identify that the protein phosphatase 2A (PP2A) can interact with TET2 and dephosphorylates S99. Collectively, our study provides novel insights into the role of the N-terminal domain in TET2 regulation. Moreover, they demonstrate the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels and/or activity.
2020-01-13 | PXD016160 | Pride
Project description:Tet2 is an enzyme that hydroxylates methylated cytosines and has been implicated in hematopoietic differentiation and the formation of myeloid malignancies when mutated. An ideal system to study the role of Tet2 in myelopoeisis is C/EBPa induced transdifferentiation of pre-B cells into macrophages, where many myeloid genes become rapidly upregulated. Here we found that C/EBPa binds to upstream regions of Tet2 and that the gene becomes activated. Tet2 knockdowns impaired the upregulation of macrophage markers as well as phagocytic capacity, suggesting that the enzyme is required for both early and late stages of myeloid differentiation. A slightly weaker effect was seen in primary cells with a Tet2 ablation. Expression arrays of transdifferentiating cells with Tet2 knockdowns permitted the identification of a small subset of myeloid genes whose upregulation was blunted. Activation of these target genes was accompanied by a rapid increase of promoter hydroxy-methylation. Our observations indicate that Tet2 helps C/EBPa to rapidly de-repress myeloid genes during the conversion of pre-B cells into macrophages. Gene expression was measured in a control and Tet2kd mouse preB cell line (called Haftl) harboring an inducible form of C/EBPa. Expression was measured in starting cells and cells induced to transdifferentiate into macrophage-like cells for 24 hours. Technical duplicates for each treatment and time were assayed.
2012-07-26 | E-GEOD-39666 | biostudies-arrayexpress
Project description:Tet2 negatively regulates memory fidelity
| PRJNA590200 | ENA
Project description:DNA methylation is a key regulatory event controlling a variety of physiological processes and can have dramatic effects on gene transcription. Methylated Cytosine (5mC) can be oxidized by the TET family of enzymes to 5-hydroxymethylcytosine (5-hmC), a key intermediate in the de-methylation cycle, and 5-hmC levels are reduced in malignancies such as AML and melanoma. We constructed a tissue microarray of human cutaneous Squamous Cell Carcinoma (SCC) tumors and found a global reduction in 5-hmC levels compared to adjacent skin. Using a murine K14-CreER system, we have found that loss of Tet2 promotes carcinogen-induced SCC, and cooperates with loss of Tp53 in to drive spontaneous SCC tumors in epithelial tissues. Loss of Tet2 in the normal epidermis leads to site-specific changes in 5-hmC levels, with many genes showing both increased and decreased levels of 5-hmC. Importantly, many of these changes were in genes regulating keratinocyte differentiation and self-renewal, consistent with reported roles for Tet enzymes in controlling lineage commitment in hematopoietic stem cells and ES cells. These results establish a functional role for Tet2 in the regulation of 5-hmC in the epidermis and demonstrate that Tet2 is a bone fide tumor suppressor in SCC.
2021-09-23 | GSE167949 | GEO
Project description:PurposePrevious studies have shown the role of ten-eleven translocation 2 (TET2) in CD4+ T cells. However, its function in CD4+ T cells under allergic inflammation is unclear. We aimed to investigate the epigenomic distribution of DNA 5-hydroxymethylcytosine (5hmC) and the role of TET2 in CD4+ T cells of allergic rhinitis (AR).MethodsThe hMeDIP-seq was performed to identify sequences with 5hmC deposition in CD4+ T cells of AR patients. Tet2-deficient or wild type mice were stimulated with ovalbumin (OVA) to develop an AR mouse model. The histopathology in nasal mucosae, Th1/Th2/Treg/Th17 cell percentage, concentrations of Th-related cytokines, expression of Tets and differential hydroxymethylated genes (DhMG), and the global deposition of 5hmC in sorted CD4+ T cells were detected.ResultsEpigenome-wide 5hmC landscape and DhMG in the CD4+ T cells of AR patients were identified. Tet2 depletion did not led to spontaneous inflammation. However, under the stimulation of allergen, OVA, loss of Tet2 resulted in the exacerbation of allergic inflammation, which was characterized by severer allergic symptoms, more inflammatory cells infiltrating the nasal lamina propria, sharper imbalances between Th1/Th2 and Treg/Th17 cells, and excessive secretion of OVA-specific IgE and Th2-related cytokines. Moreover, altered mRNA production of several DhMG and sharp decrease in 5hmC deposition were also observed in Tet2-deficient OVA-exposed mice.ConclusionsTET2 may regulate DNA 5hmC, DhMG expressions, and CD4+ T cell balance in AR.
| S-EPMC8914607 | biostudies-literature
Project description:In this study: (1) we distinguished Tet2 target genes that are regulated by its catalytic vs. noncatalytic functions in ESCs by transcriptomic profiling of Tet2 wildtype (WT), Tet2 catalytic mutant (Mut), and Tet2 knockout (KO) mouse ESCs by RNA-seq. (2) We mapped genome-wide DNA methylation of Tet2-WT, Tet2-Mut, and Tet2-KO ESCs by WGBS, to establish a critical role for Tet2 in demethylating promoters and enhancers of its catalytic target genes. (3) We determined how the genome-wide occupancy of the epigenetic modifiers Sin3a and Sap30 and the enrichment of H3K27ac, are affected in Tet2-Mut and Tet2-KO ESCs versus Tet2-WT by CUT&Tag and identified that Tet2 deficiency diminishes Sin3a occupancy at promoters and enhancers. (4) We mapped Sin3a levels genome-wide in Tet1/2 double catalytic mutant (DMUT) and Tet1/2 double knockout (DKO) ESCs, and found that deficiency of both Tet1 and Tet2 resulted in decreased levels of Sin3a in a subset of active enhancers.
2023-06-23 | GSE213398 | GEO