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MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a neoplastic phenotype in T-ALL.

ABSTRACT: BACKGROUND:While aberrant DNA methylation is a characteristic feature of tumor cells, our knowledge of how these DNA methylation patterns are established and maintained is limited. DNA methyltransferases and ten-eleven translocation methylcytosine dioxygenases (TETs) function has been found altered in a variety of cancer types. RESULTS:Here, we report that in T cell acute lymphoblastic leukemia (T-ALL) the MYC oncogene controls the expression of TET1 and TET2 to maintain 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) patterns, which is associated with tumor cell-specific gene expression. We found that cellular senescence and tumor regression upon MYC inactivation in T-ALL was associated with genome-wide changes in 5mC and 5hmC patterns. Correlating with the changes in DNA (hydroxy)methylation, we found that T-ALL overexpress TET1, while suppressing TET2 in a MYC-dependent fashion. Consequently, MYC inactivation led to an inverse expression pattern, decreasing TET1, while increasing TET2 levels. Knockdown of TET1 or ectopic expression of TET2 in T-ALL was associated with genome-wide changes in 5mC and 5hmC enrichment and decreased cell proliferation, suggesting a tumor promoting function of TET1, and a tumor suppressing role for TET2. Among the genes and pathways controlled by TET1, we found ribosomal biogenesis and translational control of protein synthesis highly enriched. CONCLUSIONS:Our finding that MYC directly deregulates the expression of TET1 and TET2 in T-ALL provides novel evidence that MYC controls DNA (hydroxy)methylation in a genome-wide fashion. It reveals a coordinated interplay between the components of the DNA (de)methylating machinery that contribute to MYC-driven tumor maintenance, highlighting the potential of specific TET enzymes for therapeutic strategies.

SUBMITTER: Poole CJ

PROVIDER: S-EPMC6604319 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a neoplastic phenotype in T-ALL.

Poole Candace J CJ Lodh Atul A Choi Jeong-Hyeon JH van Riggelen Jan J

Epigenetics & chromatin 20190702 1

<h4>Background</h4>While aberrant DNA methylation is a characteristic feature of tumor cells, our knowledge of how these DNA methylation patterns are established and maintained is limited. DNA methyltransferases and ten-eleven translocation methylcytosine dioxygenases (TETs) function has been found altered in a variety of cancer types.<h4>Results</h4>Here, we report that in T cell acute lymphoblastic leukemia (T-ALL) the MYC oncogene controls the expression of TET1 and TET2 to maintain 5-methylc ...[more]

PMID: 31266538

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Project description:BackgroundInduced hepatic stem cells (iHepSCs) with the capacities of self-renewal and bidifferentiation into hepatocytes and cholangiocytes were generated from mouse embryonic fibroblasts (MEFs) by lineage reprogramming in our previous research. However, the mechanism of iHepSC self-renewal has not been elucidated. Active demethylation regulated by Tet1 plays an important role in the self-renewal of stem cells, including pluripotent stem cells and adult stem cells. Here, we investigated the role and mechanism of Tet1-regulated demethylation in the self-renewal of iHepSCs.MethodsThe methylation levels and the expression of Tet1 in iHepSCs and MEFs were analyzed by immunofluorescent staining, quantitative reverse transcription PCR and western blotting. Then, the effects of Tet1 knockdown on the proliferation and self-renewal of iHepSCs were analyzed by CCK8, colony formation, and sphere formation assays. The mechanism by which Tet1 regulates the self-renewal of iHepSCs was investigated by chromatin immunoprecipitation, bisulfite sequence PCR, and methylation-sensitive restriction endonuclease-PCR.ResultsThe high level of 5hmC and the low level of 5mC in iHepSCs were accompanied by high expression of Tet1. After Tet1 expression was knocked down by shRNA in iHepSCs, the proliferation and self-renewal capacities were inhibited, and the expression of Myc was also decreased. The higher expression level of Myc in iHepSCs maintained its self-renewal and was regulated by Tet1, which directly binds to CBS-1 and site A regions of the Myc promoter and demethylates the CpG cytosine. In addition, CTCF also binds to the CBS-1 and site A regions of the Myc promoter and regulates Myc expression along with TET1.ConclusionThe self-renewal of iHepSCs was maintained by the higher expression of Myc, which was coregulated by TET1 and CTCF. This study may provide new insights into the self-renewal of stem cells, which can promote the research and application of 'reprogrammed' stem cells.

Dataset Information

MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a neoplastic phenotype in T-ALL.

Publications

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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