Expression data from LPS/IFNgamma-treated Tet2-/- and Tet2+/+ mouse macrophages.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE81398 | GEO | 2017/01/24
SECONDARY ACCESSION(S): PRJNA321440
REPOSITORIES: GEO
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Project description:We examined the effect of ablation of Tet2, an epigenetic regulator of gene transcription, in the global programme of gene expression at baseline, without pro-inflammatory activation, in macrophages.
2017-01-24 | GSE89824 | 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: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:Two different macrophage populations contribute to CNS neuroinflammation: CNS-resident microglia and CNS-infiltrating peripheral macrophages. Markers distinguishing these two populations in tissue sections have not been identified. Therefore, we compared gene expression between LPS (lipopolysaccharide)/interferon (IFN)gamma-treated microglia from neonatal mixed glial cultures and similarly treated peritoneal macrophages. Fifteen molecules were identified by quantative PCR (qPCR) as being enriched from 2-fold to 250-fold in cultured neonatal microglia when compared with peritoneal macrophages. Only three of these molecules (C1qA, Trem2, and CXCL14) were found by qPCR to be also enriched in adult microglia isolated from LPS/IFNgamma-injected CNS when compared with infiltrating peripheral macrophages from the same CNS. The discrepancy between the in vitro and in vivo qPCR data sets was primarily because of induced expression of the 'microglial' molecules (such as the tolerance associated transcript, Tmem176b) in CNS-infiltrating macrophages. Bioinformatic analysis of the approximately 19000 mRNAs detected by TOGA gene profiling confirmed that LPS/IFNgamma-activated microglia isolated from adult CNS displayed greater similarity in total gene expression to CNS-infiltrating macrophages than to microglia isolated from unmanipulated healthy adult CNS. In situ hybridization analysis revealed that nearly all microglia expressed high levels of C1qA, while subsets of microglia expressed Trem2 and CXCL14. Expression of C1qA and Trem2 was limited to microglia, while large numbers of GABA+ neurons expressed CXCL14. These data suggest that (i) CNS-resident microglia are heterogeneous and thus a universal microglia-specific marker may not exist; (ii) the CNS micro-environment plays significant roles in determining the phenotypes of both CNS-resident microglia and CNS-infiltrating macrophages; (iii) the CNS microenvironment may contribute to immune privilege by inducing macrophage expression of anti-inflammatory molecules.
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Project description:we compared self-renewal and lineage specification of WT and Tet2-deficient HSPCs during ageing and demonstrated that Tet2 ablation alters age-dependent HSC functional decline, revealing a disparate ageing process in the Tet2-deficient haemopoietic system.
2023-08-11 | GSE183675 | GEO
Project description:Deleterious somatic mutations in DNMT3A or TET2 are associated with clonal expansion of haematopoietic cells and higher risk of cardiovascular disease (CVD). In mice, most studies have indicated an over-activation of the inflammatory program in myeloid cells with reduced DNMT3A or TET2 expression. However, the effect of loss of function of DNMT3A and TET2 in human myeloid cells remains poorly understood. Here, we investigated the roles of DNMT3A and TET2 in normal human monocyte- derived macrophages (mDM), in mDM isolated from individuals with DNMT3A or TET2 mutations and in macrophages isolated from human atherosclerotic plaques. Using a combination of transcriptomic, epigenetic, and imaging assays, we provide evidence that, in addition to distinct roles in regulation of macrophage gene expression, DNMT3A and TET2 share a common role in maintaining mitochondrial DNA integrity by regulating the expression of Transcription Factor A, Mitochondria ( TFAM ). This shared function is dependent on interactions of DNMT3A and TET2 with RBPJ and ZNF143 at regulatory elements in the TFAM gene. Experimental reduction of DNMT3A or TET2 expression in normal human mDMs results in downregulation of TFAM, release of mtDNA into the cytoplasm and consequent activation of a type I interferon response mediated by cGAS. Single-cell RNA-seq analysis of mDMs from individuals with heterozygous loss-of-function mutations in DNMT3A and TET2 revealed a similar transcriptional signature. In addition, single-cell RNA-seq analysis of normal mDM and macrophages residing in human atherosclerotic plaques revealed higher expression of type I IFN signature genes specifically in cells with lower DNMT3A or TET2 expression. The production of IFN as a component of the type I IFN response induces activation of interferon-stimulated genes in neighbouring cells, representing a mechanism by which partial loss of function of DNMT3A or TET2 in a small fraction of cells could exert pathogenic effects in the artery wall. These findings suggest that targeting the type I IFN pathway may have therapeutic value in reducing risk of cardiovascular disease in patients with DNMT3A or TET2 mutations.
2022-08-05 | GSE206030 | GEO
Project description:we compared self-renewal and lineage specification of WT and Tet2-deficient HSPCs during ageing and demonstrated that Tet2 ablation alters age-dependent HSC functional decline, revealing a disparate ageing process in the Tet2-deficient haemopoietic system.
2023-09-10 | GSE157592 | 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.
2012-07-27 | GSE39666 | GEO
Project description:Execution of lineage-specific differentiation programs requires tight coordination between many regulators including Ten-eleven translocation (TET) family enzymes catalyzing 5-methylcytosine oxidation in DNA. Here, by using Keratin 14-Cre-driven ablation of Tet genes in skin epithelial cells, we demonstrate that ablation of Tet2/Tet3 result in marked alterations of hair shape and length followed by hair loss. We show that through DNA demethylation, Tet2/Tet3 control chromatin accessibility, Dlx3 binding and promoter activity of the Krt25 and Krt28 genes regulating hair shape, as well as regulate interactions between the Krt28 gene promoter and distal enhancer. Moreover, Tet2/Tet3 also control three-dimensional chromatin topology in Keratin type I/II gene loci via DNA methylation-independent mechanisms. These data demonstrate the essential roles for Tet2/3 in establishment of lineage-specific gene expression program and control of Dlx3/Krt25/Krt28 axis in hair follicle epithelial cells and implicate modulation of DNA methylation as a novel approach for hair growth control.
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