Whole-genome fingerprint of the DNA methylome during human B cell differentiation.
Whole-genome fingerprint of the DNA methylome during human B cell differentiation.
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DOI：
10.1038/ng.3291
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发表时间：
2015-07
期刊：
影响因子：
30.8
通讯作者：
Martín-Subero JI
中科院分区：
文献类型：
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作者：
Kulis M;Merkel A;Heath S;Queirós AC;Schuyler RP;Castellano G;Beekman R;Raineri E;Esteve A;Clot G;Verdaguer-Dot N;Duran-Ferrer M;Russiñol N;Vilarrasa-Blasi R;Ecker S;Pancaldi V;Rico D;Agueda L;Blanc J;Richardson D;Clarke L;Datta A;Pascual M;Agirre X;Prosper F;Alignani D;Paiva B;Caron G;Fest T;Muench MO;Fomin ME;Lee ST;Wiemels JL;Valencia A;Gut M;Flicek P;Stunnenberg HG;Siebert R;Küppers R;Gut IG;Campo E;Martín-Subero JI
我们通过全基因组亚硫酸氢盐测序和高密度微阵列分析了跨越整个B细胞分化程序的10个亚群的DNA甲基化组。我们观察到非CpG甲基化在B细胞定型后消失，而CpG甲基化在B细胞成熟过程中发生了广泛的变化，显示出累积模式，并影响约30%的所有测量的CpG。早期分化阶段主要表现为增强子去甲基化，这与关键B细胞转录因子的上调有关，并影响B细胞生物学中涉及的多个基因。晚期分化阶段，相反，表现出广泛的异染色质的去甲基化和多梳抑制区域的甲基化增益，并没有影响基因在B细胞中具有明显的功能影响。这种特征此前曾被认为与衰老和癌症有关，在寿命延长的成熟细胞中尤其普遍。将B细胞肿瘤与其正常对应物进行比较，我们发现它们经常在正常B细胞分化期间已经经历动态甲基化的区域中获得甲基化变化。
We analyzed the DNA methylome of ten subpopulations spanning the entire B-cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B-cell commitment whereas CpG methylation changed extensively during B-cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpGs. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B-cell transcription factors and affected multiple genes involved in B-cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain of polycomb-repressed areas, and did not affect genes with apparent functional impact in B cells. This signature, which has been previously linked to aging and cancer, was particularly widespread in mature cells with extended life span. Comparing B-cell neoplasms with their normal counterparts, we identified that they frequently acquire methylation changes in regions undergoing dynamic methylation already during normal B-cell differentiation.