Lee Seung-Tae, Muench Marcus O, Fomin Marina E, Xiao Jianqiao, Zhou Mi, de Smith Adam, Martín-Subero José I, Heath Simon, Houseman E Andres, Roy Ritu, Wrensch Margaret, Wiencke John, Metayer Catherine, Wiemels Joseph L
Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA 94158, USA Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul 120752, Republic of Korea.
Blood Systems Research Institute, University of California at San Francisco, San Francisco, CA 94158, USA Liver Center and Department of Laboratory Medicine, University of California at San Francisco, San Francisco, CA 94158, USA.
Nucleic Acids Res. 2015 Mar 11;43(5):2590-602. doi: 10.1093/nar/gkv103. Epub 2015 Feb 17.
We investigated DNA methylomes of pediatric B-cell acute lymphoblastic leukemias (B-ALLs) using whole-genome bisulfite sequencing and high-definition microarrays, along with RNA expression profiles. Epigenetic alteration of B-ALLs occurred in two tracks: de novo methylation of small functional compartments and demethylation of large inter-compartmental backbones. The deviations were exaggerated in lamina-associated domains, with differences corresponding to methylation clusters and/or cytogenetic groups. Our data also suggested a pivotal role of polycomb and CTBP2 in de novo methylation, which may be traced back to bivalency status of embryonic stem cells. Driven by these potent epigenetic modulations, suppression of polycomb target genes was observed along with disruption of developmental fate and cell cycle and mismatch repair pathways and altered activities of key upstream regulators.
我们使用全基因组亚硫酸氢盐测序、高清微阵列以及RNA表达谱，对儿童B细胞急性淋巴细胞白血病（B-ALL）的DNA甲基化组进行了研究。B-ALL的表观遗传改变发生在两条轨迹上：小功能区室的从头甲基化和大的区间主干的去甲基化。这些偏差在与核纤层相关的结构域中被放大，差异与甲基化簇和/或细胞遗传学组相对应。我们的数据还表明，多梳蛋白和CTBP2在从头甲基化中起关键作用，这可能追溯到胚胎干细胞的双价状态。在这些强大的表观遗传调控作用下，观察到多梳蛋白靶基因的抑制，同时发育命运、细胞周期和错配修复途径受到破坏，关键上游调节因子的活性发生改变。
