TY - JOUR
T1 - Acute Depletion Redefines the Division of Labor among DNA Methyltransferases in Methylating the Human Genome
AU - Tiedemann, Rochelle L.
AU - Putiri, Emily L.
AU - Lee, Jeong Heon
AU - Hlady, Ryan A.
AU - Kashiwagi, Katsunobu
AU - Ordog, Tamas
AU - Zhang, Zhiguo
AU - Liu, Chen
AU - Choi, Jeong Hyeon
AU - Robertson, Keith D.
N1 - Funding Information:
We thank Dr. B. Volgelstein for the HCT116 DNMT KO cell lines and Dr. D. Gius for the HCT116 DNMT overexpression cell lines. We also thank Eiko Kitamura (Georgia Regents University Cancer Center) for assistance with expression microarrays and Joshua Hysong for data analysis support. This work was supported by NIH grants R01 CA114229 (to K.D.R.), R01 AA19976 (to K.D.R. and C.L.), and F31 CA171727 (to R.L.T.), the Mayo Clinic Center for Individualized Medicine, and the Mayo Clinic Cancer Center.
Publisher Copyright:
© 2014 The Authors.
PY - 2014/11/20
Y1 - 2014/11/20
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2014.10.013
DO - 10.1016/j.celrep.2014.10.013
M3 - Article
C2 - 25453758
AN - SCOPUS:84964698666
VL - 9
SP - 1554
EP - 1566
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 4
ER -