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TET2 Mutations Affect Non-CpG Island DNA Methylation at Enhancers and Transcription Factor–Binding Sites in Chronic Myelomonocytic Leukemia
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Abstract
TET2 enzymatically converts 5-methylcytosine to 5-hydroxymethylcytosine as well as other covalently modified cytosines and its mutations are common in myeloid leukemia. However, the exact mechanism and the extent to which TET2 mutations affect DNA methylation remain in question. Here, we report on DNA methylomes in TET2 wild-type (TET2-WT) and mutant (TET2-MT) cases of chronic myelomonocytic leukemia (CMML). We analyzed 85,134 CpG sites [28,114 sites in CpG islands (CGI) and 57,020 in non-CpG islands (NCGI)]. TET2 mutations do not explain genome-wide differences in DNA methylation in CMML, and we found few and inconsistent differences at CGIs between TET2-WT and TET2-MT cases. In contrast, we identified 409 (0.71%) TET2-specific differentially methylated CpGs (tet2-DMCs) in NCGIs, 86% of which were hypermethylated in TET2-MT cases, suggesting a strikingly different biology of the effects of TET2 mutations at CGIs and NCGIs. DNA methylation of tet2-DMCs at promoters and nonpromoters repressed gene expression. Tet2-DMCs showed significant enrichment at hematopoietic-specific enhancers marked by H3K4me1 and at binding sites for the transcription factor p300. Tet2-DMCs showed significantly lower 5-hydroxymethylcytosine in TET2-MT cases. We conclude that leukemia-associated TET2 mutations affect DNA methylation at NCGI regions containing hematopoietic-specific enhancers and transcription factor–binding sites. Cancer Res; 75(14); 2833–43. ©2015 AACR.
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“We found that DMRs in Tet2-KO LSKs, CMPs, and GMPs relative to WT were preferentially located in enhancer sites, with less within CpG islands, as described previously32–34.”
From Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells (2023) · cites this paper as [33]
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Role of TET enzymes in DNA methylation, development, and cancer
Rasmussen, K. D., & Helin, K. (2016) · Genes & Development · doi:10.1101/gad.276568.115 · Cited by 1,040
“In contrast, they did not detect changes in DNAmethylation at CpG islands (Yamazaki et al. 2015).”
BackgroundTet2 restrains inflammatory gene expression in macrophages
Cull, A. H., Snetsinger, B., Buckstein, R., Wells, R. A., & Rauh, M. J. (2017) · Experimental Hematology · doi:10.1016/j.exphem.2017.08.001 · Cited by 295
Reprogramming the epigenome with vitamin C
Lee Chong, T., Ahearn, E. L., & Cimmino, L. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00128 · Cited by 120
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Metadata
- Authors
- Yamazaki, J., Jelinek, J., Lu, Y., Cesaroni, M., Madzo, J., Neumann, F., He, R., Taby, R., Vasanthakumar, A., Macrae, T., Ostler, K. R., Kantarjian, H. M., Liang, S., Estecio, M. R., Godley, L. A., & Issa, J.-P. J.
- Venue
- Cancer Research
- Published
- 2015-07-14
- Volume
- 75
- Issue
- 14
- Pages
- 2833-2843
- ISSN
- 0008-5472
- 1538-7445
- PMC
- PMC4506197
- Cited by
- 89
- References
- 10
- Language
- en
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