MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a neoplastic phenotype in T-ALL
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE126029 | GEO | 2019/07/01
REPOSITORIES: GEO
Similar Datasets
Project description:TET1/2/3 are methylcytosine dioxygenases regulating cytosine hydroxymethylation in the genome. Tet1 and Tet2 are abundantly expressed in HSC/HPCs and implicated in the pathogenesis of hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1 and TET2 were often concomitantly down-regulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/Tet2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2-/- HSC/HPCs had overlapping and unique 5hmC and 5mC profiles and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed onset of myeloid malignancies compared to Tet2-/- mice and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1 or TET2 individually and their cross-talks in the pathogenesis of hematological malignancies. Given the role of Tet proteins in 5mC oxidation, we employed a previously established chemical labeling and affinity purification method coupled with high-throughput sequencing (hMe-Seal) to profile the genome-wide distribution of 5hmC, as well as methylated DNA immunoprecipitation (MeDIP) coupled with high-throughput sequencing (MeDIP-seq) to profile 5mC using BM LK cells purified from young WT, Tet2-/- and DKO mice (6-10 wks old).
2015-11-12 | E-GEOD-73611 | biostudies-arrayexpress
Project description:Through the analysis of mouse liver tumours promoted by distinct routes (DEN exposure alone, DEN exposure plus non-genotoxic insult with phenobarbital and non-alcoholic fatty liver disease); we report that the cancer associated hyper-methylated CGI events in mice are also predicated by silent promoters that are enriched for both the DNA modification 5-hydroxymethylcytosine (5hmC) and the histone modification H3K27me3 in normal liver. During cancer progression these CGIs undergo hypo-hydroxymethylation, prior to subsequent hyper-methylation; whilst retaining H3K27me3. A similar loss of promoter-core 5hmC is observed in Tet1 deficient mouse livers indicating that reduced Tet1 binding at CGIs may be responsible for the epigenetic dysregulation observed during hepatocarcinogenesis. Consistent with this reduced Tet1 protein levels are observed in mouse liver tumour lesions. As in human, DNA methylation changes at CGIs do not appear to be direct drivers of hepatocellular carcinoma progression in mice. Instead dynamic changes in H3K27me3 promoter deposition are strongly associated with tumour-specific activation and repression of transcription. Our data suggests that loss of promoter associated 5hmC in diverse liver tumours licences DNA methylation reprogramming at silent CGIs during cancer progression. We carry out 5-hydroxymethylation DNA immunoprecipitation (hmeDIP) prior to sequencing Ion Proton P1 to report on the genome-wide 5hmC patterns. Heterozygote pairs of Tet1 B6;129S4-Tet1tm1.1Jae/J mice were bought from The Jackson Laboratory (Maine USA). Heterozygotes were interbred to produce homozygous knock out males with colony mate wild type controls. Genome-wide 5hmC patterns were generated by hydroxymethyl-DNA immuoprecipitation (hmeDIP) followed by genome wide sequencing on the Ion Proton P1 sequencer.
2016-05-17 | E-GEOD-77730 | biostudies-arrayexpress
Project description:TET1/2/3 are methylcytosine dioxygenases regulating cytosine hydroxymethylation in the genome. Tet1 and Tet2 are abundantly expressed in HSC/HPCs and implicated in the pathogenesis of hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1 and TET2 were often concomitantly down-regulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/Tet2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2-/- HSC/HPCs had overlapping and unique 5hmC and 5mC profiles and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed onset of myeloid malignancies compared to Tet2-/- mice and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1 or TET2 individually and their cross-talks in the pathogenesis of hematological malignancies.
2015-11-12 | GSE73611 | GEO
Project description:Tet enzymes (Tet1/2/3) convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Tet1 and Tet2 mediate 5hmC generation in mouse embryonic stem cells (ESCs) and various embryonic and adult tissues. To investigate the effects of combined deficiency of Tet1 and Tet2 on pluripotency and development, we have generated Tet1 and Tet2 double knockout (DKO) ESCs and mice. DKO ESCs were depleted of 5hmC, but remained pluripotent with subtle defects in differentiation and changes in gene expression. Double mutant embryos and chimeras exhibited mid-gestation defects and postnatal DKO mice displayed partially penetrant neonatal lethality and stochastic perturbation of imprinting. Viable DKO animals developed normally to adulthood but had reduced 5hmC level, increased 5mC level and lacked 5hmC in germ cells. Nevertheless, DKO mice of both sexes were fertile with females having smaller ovaries and reduced fertility. Our data suggest that both Tet1 and Tet2 contribute to 5hmC levels during development. Their combined loss does not block differentiation and embryogenesis, but leads to partially penetrant embryonic and perinatal abnormalities and compromised viability. Moreover, the presence of substantial levels of 5hmC in DKO embryos and adult mice suggests a significant contribution of Tet3 in hydroxylation of 5mC during development. Methylation patterns in tissue samples from a series of wt and Tet1/Tet2 DKO embryos, neonates and adults were generated using methylated DNA immunoprecipitation with antibodies against 5mC (MeDIP) and 5hmC (hMeDIP) followed by deep sequencing.
2013-02-01 | E-GEOD-42396 | biostudies-arrayexpress
Project description:Nephron endowment is a key determinant of later life hypertension and kidney disease. Here we studied whether epigenetic changes, specifically the ten–eleven translocation (Tet) DNA demethylase family, Tet1, Tet2, and Tet3-mediated active DNA hydroxymethylation is necessary for gene expression regulation and kidney differentiation. We generated mice with deletion of Tet1, Tet2 or Tet3 in Six2 positive nephron progenitors (NP). We did not observe changes in development or kidney function in mice with nephron progenitor-specific deletion of Tet1, Tet2, Tet3 or Tet1/Tet2 or Tet1/Tet3. On the other hand, mice with combined Tet2 and Tet3 loss in Six2-positive NPCs failed to form nephrons leading to kidney failure and perinatal death. Tet2 and Tet3 loss in Six2-positive NPs resulted in defect in mesenchymal to epithelial transition and renal vesicle differentiation. Whole genome bisulfite sequencing, single cell RNA sequencing, and gene and protein expression assay identified a defect in expression in genes in the WNT-β-catenin signaling pathway in absence of Tet2 and Tet3 due to a failure in demethylation of these loci. Our results indicate the key role of Tet2 and Tet3-mediated active cytosine hydroxymethylation in NPs in kidney development and nephron endowment.
2022-11-23 | GSE212715 | GEO
Project description:Adult myelination is essential for brain function and response to injury, but the molecular mechanisms remain elusive. Here we identify DNA hydroxy-methylation, an epigenetic mark catalyzed by Ten-Eleven translocation (TET) enzymes, as necessary for adult myelin repair. While DNA hydroxy-methylation and high levels of TET1 were detected in young adult mice during myelin regeneration after demyelination, this process was defective in old mice. Constitutive or inducible lineage-specific ablation of Tet1 (but not of Tet2) recapitulated the age-related decline of DNA hydroxy-methylation and inefficient remyelination. Genome-wide hydroxy-methylation and transcriptomic analysis identified solute carrier gene families as TET1 targets. Lower transcripts for these genes in Tet1 mutants and old mice were associated with swelling at the neuroglial interface, a phenotype detected also in zebrafish Slc12a2b mutants. We conclude that TET1-mediated DNA hydroxy-methylation is necessary for adult myelination after injury, by modulating the levels of the solute carrier SLC12A2 at the axo-myelin interface.
2020-03-14 | GSE137611 | GEO
Project description:MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a neoplastic phenotype in T-ALL
| PRJNA520933 | ENA
Project description:This study uses whole-transcriptome sequencing to characterize the transcriptomes of mouse embryonic fibroblasts (MEF's). Two conditions were analyzed, MEF cells with intact TET1/TET2 enzymes (WT) and MEF cells with TET1/TET2 knocked out (DKO). Our results identify sets of differentially expressed genes which are correlated with TET1/TET2 induced methylation changes of the corresponding genes. Whole transcriptome analysis of M. musculus MEF cells. Two conditions were sequenced and analyzed, the first is wild type (WT), the second corresponds to knock-out of TET1 and TET2 enzymes.
2015-12-07 | E-GEOD-58609 | biostudies-arrayexpress
Project description:Adult myelination is recognized as essential for brain function and response to injury and yet, its molecular understanding is mostly inferred from developmental studies. In this study, we identify DNA hydroxy-methylation, an epigenetic mark catalyzed by Ten-Eleven translocation (TET) enzymes, as necessary for adult, but not for developmental, myelin formation. While hydroxy-methylation and high levels of TET1 were detected in young adult mice during myelin regeneration after lysolecithin-induced demyelination, this process was defective in older mice. Lineage specific ablation of the enzyme Tet1 (but not of Tet2) recapitulated the age-related decline of TET1 and inefficient remyelination, without impacting developmental myelination. Genome-wide DNA hydroxy-methylation profiling of adult progenitors and mature oligodendrocytes, identified solute carriers regulating neuronal-glial communication as gene targets, whose expression was dramatically decreased in mutants and in older mice. We conclude that TET1-mediated hydroxy-methylation is critical for adult myelination in response to injury.
2020-03-14 | GSE122446 | GEO
Project description:The discovery of cytosine hydroxymethylation (5-hmC) as a mechanism that potentially controls DNA methylation changes typical of neoplasia prompted us to investigate its behavior in colon cancer. 5-hmC is globally reduced in proliferating cells such as colon tumors and the gut crypt progenitors, from which tumors can arise. Here, we show that colorectal tumors and cancer cells express Ten-Eleven Translocation (TET) transcripts at levels similar to normal tissues. Genome-wide analyses show that promoters marked by 5-hmC in normal tissue, and those identified as TET2 targets in colorectal cancer cells, are resistant to methylation gain in cancer. In vitro studies of TET2 in cancer cells confirm that these promoters are resistant to methylation gain independently of sustained TET2 expression. We also find that a considerable number of the methylation gain-resistant promoters marked by 5-hmC in normal colon overlap with those that are marked with poised bivalent histone modifications in embryonic stem cells. Together our results indicate that promoters that acquire 5-hmC upon normal colon differentiation are innately resistant to neoplastic hypermethylation by mechanisms that do not require high levels of 5-hmC in tumors. Our study highlights the potential of cytosine modifications as biomarkers of cancerous cell proliferation. 5 normal colon samples and 4 matching tumor samples were profiled for 5-hydroxymethylcytosine content genomewide using hmeDIP-seq. The colorectal cancer cell line HCT116 was profiled for binding of TET2 genomewide by chromatin immunoprecipitation sequencing (ChIP-seq).
2015-02-03 | E-GEOD-47590 | biostudies-arrayexpress