Comparative analysis of Tet2 catalytic deficient and knockout bone marrow over time
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ABSTRACT:
PROVIDER: PRJNA947607 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we investigated the role of Tet2 in regulation of hematopoietic genes by performing transcriptomic analysis of Tet2 WT, Mut, and KO LSK and Lin– cells at 3, 6, 9, and 12 months by RNA-seq, and mapping the DNA methylation landscape of 3-month-old Tet2 WT, Mut, and KO LSK and Lin– cells. (1) We find that loss of Tet2 (Tet2 KO) vs. a loss of Tet2 catalytic function (Tet2 Mut) at different time points and cell types causes distinct gene expression changes when compared to WT samples as assessed by RNA-seq. (2) Additionally, we find that many genes implicated in lymphoma and leukemia are deregulated in Tet2 Mut and KO LSK and Lin– cells, consistent with the phenotypes observed in mice transplanted with Tet2 Mut and KO bone marrow. (3) We also mapped genome-wide DNA methylation levels of WT, Tet2 Mut, and KO LSK and Lin– cells at 3 months by WGBS and establish a role for Tet2 in demethylating genes implicated in lymphoma and leukemia initiation and progression.
2023-06-01 | GSE227977 | GEO
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Project description:To identify genes that are influenced by the catalytic and non-catalytic functions of Tet2 in hematopoietic stem and progenitor cells (HSPCs), we analyzed the gene expression profiles of Tet2 catalytic mutant (Tet2 Mut), Tet2 knockout (Tet2 KO) and wild-type HSPCs (or LSK, Lin–Sca-1+c-Kit+) and multi-potent progenitor (or MPP, Lin–) cells by RNA-seq.
2019-08-05 | GSE132090 | GEO
Project description:TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities.
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Project description:The TET2 gene encodes an α-ketoglutarate-dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B- and T-cell malignancies. TET2 somatic mutations are also identified in healthy elderly individuals with clonal hematopoiesis. Tet2-deficient mouse models showed widespread hematological differentiation abnormalities, including myeloid, T-cell, and B-cell malignancies. We show here that, similar to what is observed with constitutive Tet2-deficient mice, B-cell-specific Tet2 knockout leads to abnormalities in the B1-cell subset and a development of B-cell malignancies after long latency. Aging Tet2-deficient mice accumulate clonal CD19+ B220low immunoglobulin M+ B-cell populations with transplantable ability showing similarities to human chronic lymphocytic leukemia, including CD5 expression and sensitivity to ibrutinib-mediated B-cell receptor (BCR) signaling inhibition. Exome sequencing of Tet2-/- malignant B cells reveals C-to-T and G-to-A mutations that lie within single-stranded DNA-specific activation-induced deaminase (AID)/APOBEC (apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like) cytidine deaminases targeted motif, as confirmed by the lack of a B-cell tumor in compound Tet2-Aicda-deficient mice. Finally, we show that Tet2 deficiency accelerates and exacerbates T-cell leukemia/lymphoma 1A-induced leukemogenesis. Together, our data establish that Tet2 deficiency predisposes to mature B-cell malignancies, which development might be attributed in part to AID-mediated accumulating mutations and BCR-mediated signaling. This accession concerns 46 transcriptomic experiments with Affymetrix Mouse 430-2 array..
2019-12-12 | E-MTAB-8501 | biostudies-arrayexpress
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:Dioxygenases of the TET family impact genome functions by converting 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC). Here, we identified TET2 as a crucial regulator of mast cell differentiation and proliferation. In the absence of TET2, mast cells showed disrupted gene expression and altered genome-wide 5hmC deposition, especially at enhancers and in proximity of down-regulated genes. Impaired differentiation of Tet2-ablated cells could be compensated or further exacerbated by modulating the activity of other TET family members, and mechanistically it could be linked to the dysregulated expression of C/EBP family transcription factors. Conversely, the marked increase in proliferation induced by the loss of TET2 could be rescued exclusively by re-expression of wild-type or catalytically inactive TET2. Our data indicate that in the absence of TET2, mast cell differentiation is under the control of compensatory mechanisms mediated by other TET family members, while proliferation is strictly dependent on TET2 expression.
2016-05-04 | GSE79090 | GEO
Project description:Tet1, Tet2 and Tet1/Tet2 catalytic mutants as well as DPPA3 KO ESCs harboring a doxycyclin inducible Dppa3 transgene were induced for several days to monitor LINE-1 methylation levels.
2020-10-23 | E-MTAB-9654 | biostudies-arrayexpress
Project description:Dioxygenases of the TET family impact genome functions by converting 5-methylcytosine in DNA to 5-hydroxymethylcytosine (5hmC), but their contribution to differentiation and function of immune cells is still incompletely understood. Here, we identified TET2 as a crucial regulator of mast cell differentiation and proliferation. Specifically, mast cell differentiation was impaired in absence of TET2, a defect that could be however compensated or further exacerbated modulating the activity of other TET family members. Mechanistically, delayed mast cell differentiation was related to the dysregulated expression of C/EBP transcription factors. Vice versa, the marked increase in proliferation induced by the absence of TET2 could be rescued exclusively by the specific re-expression of TET2 itself, regardless of its enzymatic activity. Our data indicate that in absence of TET2, mast cell differentiation is largely under the control of compensatory mechanisms mediated by other TET family members, while proliferation is strictly dependent on TET2 expression.
2016-05-04 | GSE77844 | GEO
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