title: TET2 Mutations Affect Non-CpG Island DNA Methylation at Enhancers and Transcription Factor-Binding Sites in Chronic Myelomonocytic Leukemia.
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.
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Yamazaki
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cesaroni
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania. Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Jozef
authors.initials: J
authors.lastname: Madzo
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Frank
authors.initials: F
authors.lastname: Neumann
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rong
authors.initials: R
authors.lastname: He
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Taby
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Aparna
authors.initials: A
authors.lastname: Vasanthakumar
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Trisha
authors.initials: T
authors.lastname: Macrae
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Ostler
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shoudan
authors.initials: S
authors.lastname: Liang
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Marcos R
authors.initials: MR
authors.lastname: Estecio
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. jpissa@temple.edu.
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015894:Genome, Human; D006410:Hematopoiesis / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics*; D046228:Microarray Analysis; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D049308:Dioxygenases; C541081:TET2 protein, human