急性缺失重新定义了DNA甲基转移酶在人类基因组甲基化过程中的分工。
Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome.
作者信息
Tiedemann Rochelle L, Putiri Emily L, Lee Jeong-Heon, Hlady Ryan A, Kashiwagi Katsunobu, Ordog Tamas, Zhang Zhiguo, Liu Chen, Choi Jeong-Hyeon, Robertson Keith D
机构信息
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.
Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
出版信息
Cell Rep. 2014 Nov 20;9(4):1554-66. doi: 10.1016/j.celrep.2014.10.013. Epub 2014 Nov 6.
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.
由DNA甲基转移酶（DNMTs）介导的DNA甲基化全球模式在所有癌症中均被破坏，其机制在很大程度上仍不清楚，这阻碍了它们作为治疗靶点的发展。在多能人类肿瘤细胞系中对所有DNMTs进行组合式急性耗竭，随后进行表观基因组和转录组分析，详细揭示了DNMT的功能。DNMT3B的占据在分化过程中调节甲基化，而发现了一种意想不到的相互作用，其中DNMT1和DNMT3B在基因体内对立调节甲基化和羟甲基化，这一发现已在其他细胞类型中得到证实。DNMT3B介导非CpG甲基化，而DNMT3L影响DNMT3B对非CpG与CpG位点甲基化的活性。总之，这些数据揭示了每种DNMT的功能靶点，表明亚型选择性抑制在治疗上具有优势。
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