RNA-seq in murine acute myeloid leukemia (AML) cells with and without knockdown of Tet1
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE116548 | GEO | 2020/06/30
REPOSITORIES: GEO
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Project description:To dissect the mechanism underlying the regulation of TET1 on its target genes in AML, we performed 5hmC-sequencing for genomic DNA isolated from human MonoMac6 AML cells with and without knockdown of TET1.
2020-06-30 | GSE116549 | GEO
Project description:Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21 checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anti-cancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling towards senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL-ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development.
2012-04-22 | GSE35038 | GEO
Project description:Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21 checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anti-cancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling towards senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL-ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development. We created a mouse model wherein the protein function of the MLL-ENL oncogene depends on tamoxifen due to fusion with the mutated estrogen-binding domain of the estrogen receptor (ERtm). After 7 months of tamoxifen administration, the MLL-ENL-ERtm mice developed a myeloproliferative disease, which progressed into the terminal stage after a long period (mean survival: 592 ± 112 days) of continuous tamoxifen provision. We have profiled gene expression at three time-points of tamoxifen treatment corresponding to three distinct cellular states of the MLL-ENL-ERtm-induced myeloproliferation in the bone marrow: 1. 7 months - high proliferation state with low DDR signaling (4 biological replicates), 2. 7-8 months - the transition period of lower proliferation and high DDR activity (4 biogical replicates) and 3. 8 months - the senescence (3 biological replicates). Time-matched tamoxifen-treated wild-type bone marrow analysed in 4 biological replicates. We have profiled gene expression in three disease stages in the spleen: 1. 7 months - early stage - induced proliferation and DDR (3 biological replicates), 2. 9-10 months - progression - partial senescence and DDR is maintained (3 biological replicates) and 3. 16-23 months - terminal stage - proliferation, low or absent DDR and no senescence (3 biological replicates). Time-matched tamoxifen-treated and age-matched wild-type spleens analysed in 5 biological replicates.
2012-04-21 | E-GEOD-35038 | biostudies-arrayexpress
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.
2022-08-31 | PXD028850 | Pride
Project description:TET1, the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), was first identified as a partner gene in MLL-rearranged leukemia, but its definitive pathological role in leukemia is unclear. The down-regulation of all three TET genes and loss-of-function mutations of TET2 have been frequently observed in various cancers, and it was thought that they all play tumor-suppressor roles in tumorigenesis. Here we show that TET1 is likely a direct target of MLL and significantly up-regulated in MLL-rearranged leukemia, associated with an increased level of 5hmC. Our further in vitro and in vivo studies demonstrate that Tet1 plays an indispensable oncogenic role in MLL-rearranged leukemia, through cooperating with MLL fusion proteins in regulating their co-targets including the Hoxa/Meis1/Pbx3/Flt3 genes. Our data delineate a MLL-fusion/Tet1/Hoxa/Meis1/Pbx3/Flt3 signaling axis in MLL-rearranged leukemia, and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease. We report genome-wide 5hmC enrichment profiles and RNA-Seq gene expression in MLL-AF9 transformed and control mouse bone marrow mononuclear cells. These 5hmC profiles are derived from selctive chemical labeling and enrichment of 5hmC containing genomic DNA fragments, while the RNA-Seq expression profiles are generated from polyA enriched RNA
2015-12-14 | E-GEOD-42990 | biostudies-arrayexpress
Project description:TET1, the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), was first identified as a partner gene in MLL-rearranged leukemia, but its definitive pathological role in leukemia is unclear. The down-regulation of all three TET genes and loss-of-function mutations of TET2 have been frequently observed in various cancers, and it was thought that they all play tumor-suppressor roles in tumorigenesis. Here we show that TET1 is likely a direct target of MLL and significantly up-regulated in MLL-rearranged leukemia, associated with an increased level of 5hmC. Our further in vitro and in vivo studies demonstrate that Tet1 plays an indispensable oncogenic role in MLL-rearranged leukemia, through cooperating with MLL fusion proteins in regulating their co-targets including the Hoxa/Meis1/Pbx3/Flt3 genes. Our data delineate a MLL-fusion/Tet1/Hoxa/Meis1/Pbx3/Flt3 signaling axis in MLL-rearranged leukemia, and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.
2015-12-14 | GSE42990 | GEO
Project description:Surveillance 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 understanding of DNA methylation dynamics. Interestingly, in recent years evidence accumulated that TET1 also harbours non-catalytic functions. However, the role and mechanism of TET1 DNA demethylation independent functions still remain poorly understood. Here, we use genome engineering and quantitative multi-omics approaches to dissect the non-catalytic role of TET1. Strikingly, we find that the majority of transcriptional regulation depends on non-catalytic functions of TET1. To gain insights into possible mechanisms by which TET1 regulates transcription independent of DNA demethylation, we asked if the loss of TET1 is accompanied by changes in the histone modificaiton landscape. To this end, we compared the relative abundances of core histone modifications between Tet1 KO, Tet1 CM and WT mESCs using quantitative LC-MS/MS analysis. Surprisingly, we observed a profound global reduction of pH4Kac and H4K20me3 as well as H3K27me3 in Tet1 KO mESC. Vice versa, the monomethylation states of the latter two residues, H3K27me1 and H4K20me1 were significantly increased in Tet1 KO. Similar to the results from the transcriptome data, most of these changes were specific to Tet1 KO cells.
2022-08-11 | PXD028566 | Pride
Project description:Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a potent oncogene in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high level expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, an optimized derivative of NSC-370284, exhibited an even more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three folds. NSC-370284 and its derivative showed strong synergistic effects with standard chemotherapy. NSC-370284 directly targeted STAT3/5, transcriptional activators of TET1, and thus repressed TET1 expression. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.
2018-01-12 | GSE97407 | GEO
Project description:Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high level expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, a structural analog of NSC-370284, exhibited a more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three folds. NSC-370284 and UC-514321 both directly target STAT3/5, transcriptional activators of TET1, and thus repress TET1 expression. They also exhibit strong synergistic effects with standard chemotherapy. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.
2018-01-12 | GSE101480 | GEO
Project description:Infant and adult MLL-rearranged (MLLr) leukemia represents a disease with few treatment options and a dismal prognosis. Here, we present an in-depth proteomic characterization of in utero-initiated and adult-onset MLLr leukemia in a mouse model of MLL-ENL-mediated leukemogenesis. We characterize early proteomic events of MLL-ENL-mediated transformation in fetal and adult progenitors.
2024-04-02 | PXD042249 | Pride