title: Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome.
abstract: Global patterns of DNA methylation, mediated by the DNA methyltransferases (DNMTs), are disrupted in all cancers by mechanisms that remain largely unknown, hampering their development as therapeutic targets. Combinatorial acute depletion of all DNMTs in a pluripotent human tumor cell line, followed by epigenome and transcriptome analysis, revealed DNMT functions in fine detail. DNMT3B occupancy regulates methylation during differentiation, whereas an unexpected interplay was discovered in which DNMT1 and DNMT3B antithetically regulate methylation and hydroxymethylation in gene bodies, a finding confirmed in other cell types. DNMT3B mediated non-CpG methylation, whereas DNMT3L influenced the activity of DNMT3B toward non-CpG versus CpG site methylation. Altogether, these data reveal functional targets of each DNMT, suggesting that isoform selective inhibition would be therapeutically advantageous.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA; Cancer Center, Georgia Regents University, 1411 Laney Walker Boulevard, Augusta, GA 30912, USA.
authors.forename: Rochelle L
authors.initials: RL
authors.lastname: Tiedemann
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Putiri
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA; Epigenomics Translational Program, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Hlady
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Kashiwagi
authors.affiliation: Department of Physiology and Biomedical Engineering, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA; Epigenomics Translational Program, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
authors.forename: Tamas
authors.initials: T
authors.lastname: Ordog
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA; Epigenomics Translational Program, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, P.O. Box 100275, Gainesville, FL 32610, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Cancer Center, Georgia Regents University, 1411 Laney Walker Boulevard, Augusta, GA 30912, USA.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA; Epigenomics Translational Program, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA. Electronic address: robertson.keith@mayo.edu.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Robertson
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D056426:Genetic Loci; D015894:Genome, Human; D006801:Humans; D034741:RNA, Small Interfering / Q000378:metabolism*; D000097584:DNA Methyltransferase 3B
chemical_list: D044503:5-Methylcytosine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D034741:RNA, Small Interfering; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C412484:DNMT3L protein, human; C000619380:DNMT1 protein, human