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MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a
Candace J Poole1, Atul Lodh1, Jeong-Hyeon Choi2
1Department of Biochemistry and Molecular Biology, Augusta University, 1410 Laney-Walker Blvd., Augusta, GA, 30912, USA.
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.
Insights
The MYC oncogene regulates TET1 and TET2 to control DNA methylation patterns in T-ALL, impacting tumor cell gene expression and proliferation. MYC inactivation reverses TET1/TET2 expression, leading to tumor regression.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Oncology
Background:
- Aberrant DNA methylation is a hallmark of cancer, yet its establishment and maintenance mechanisms remain incompletely understood.
- The function of DNA methyltransferases and ten-eleven translocation methylcytosine dioxygenases (TETs) is frequently altered in various cancer types.
Purpose of the Study:
- To investigate the role of the MYC oncogene in regulating DNA methylation patterns in T cell acute lymphoblastic leukemia (T-ALL).
- To elucidate the interplay between MYC, TET1, and TET2 in maintaining cancer-specific epigenetic states and driving tumor progression.
Main Methods:
- Analysis of TET1 and TET2 expression in T-ALL cells.
- Investigation of MYC's regulatory effects on TET gene expression.
- Genome-wide analysis of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) patterns.
- Functional studies involving TET1 knockdown and TET2 overexpression in T-ALL models.
Main Results:
- MYC oncogene controls TET1 and TET2 expression in T-ALL, maintaining specific DNA methylation patterns linked to tumor cell gene expression.
- MYC inactivation in T-ALL induced genome-wide changes in 5mC and 5hmC, correlating with cellular senescence and tumor regression.
- T-ALL cells overexpress TET1 and suppress TET2 in a MYC-dependent manner; MYC inactivation reversed this pattern.
- TET1 overexpression promoted tumor growth, while TET2 overexpression suppressed proliferation, indicating opposing roles in T-ALL.
Conclusions:
- MYC directly deregulates TET1 and TET2 expression in T-ALL, demonstrating MYC's control over genome-wide DNA (hydroxy)methylation.
- A coordinated interplay between TET enzymes contributes to MYC-driven tumor maintenance.
- Targeting specific TET enzymes presents a potential therapeutic strategy for T-ALL.
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