The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion
The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion
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DOI：
10.1186/gb-2013-14-1-r3
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发表时间：
2013-01-01
期刊：
影响因子：
12.3
通讯作者：
Ballestar, Esteban
中科院分区：
文献类型：
--
作者：
Hernando, Henar;Shannon-Lowe, Claire;Ballestar, Esteban
背景：EB病毒(Epstein-Barr Virus，EBV)感染是多种免疫相关疾病的典型致病因素，包括淋巴瘤、淋巴增生性疾病和自身免疫性疾病。EBV介导的静息B细胞向增殖的淋巴母细胞的转化发生在感染的早期阶段，是研究与获得无限生长相关的机制的极佳模型。结果：我们通过高通量分析研究了实验性EBV感染B细胞对DNA甲基化的影响。值得注意的是，我们观察到大约250个基因的低甲基化，但没有超甲基化。低甲基化没有发生在重复序列上，这与淋巴增殖细胞中没有基因组不稳定性是一致的。甲基化的改变只发生在细胞分裂开始后，没有活跃的去甲基化机制的参与，并伴随着B细胞获得增殖的能力。基因本体论分析、表达谱分析以及对转录因子结合基序和占有率的高通量分析表明，大多数处于低甲基化状态的基因都是活性的，并显示出核因子-kappa B p65和其他B细胞特异性转录因子的存在。启动子低甲基化与与淋巴母细胞增殖表型相关的基因上调有关。有趣的是，药物诱导的去甲基化增加了静止B细胞向淋巴母细胞转化的效率，这与低甲基化和淋巴细胞增殖之间的有效合作是一致的。结论：我们的数据为B细胞转录程序导致DNA甲基化变化的作用提供了新的线索，我们发现这是EBV相关的静止B细胞向增殖淋巴母细胞转化的关键。
Background: Epstein-Barr virus (EBV) infection is a well characterized etiopathogenic factor for a variety of immune-related conditions, including lymphomas, lymphoproliferative disorders and autoimmune diseases. EBV-mediated transformation of resting B cells to proliferating lymphoblastoid cells occurs in early stages of infection and is an excellent model for investigating the mechanisms associated with acquisition of unlimited growth.Results: We investigated the effects of experimental EBV infection of B cells on DNA methylation profiles by using high-throughput analysis. Remarkably, we observed hypomethylation of around 250 genes, but no hypermethylation. Hypomethylation did not occur at repetitive sequences, consistent with the absence of genomic instability in lymphoproliferative cells. Changes in methylation only occurred after cell divisions started, without the participation of the active demethylation machinery, and were concomitant with acquisition by B cells of the ability to proliferate. Gene Ontology analysis, expression profiling, and high-throughput analysis of the presence of transcription factor binding motifs and occupancy revealed that most genes undergoing hypomethylation are active and display the presence of NF-kappa B p65 and other B cell-specific transcription factors. Promoter hypomethylation was associated with upregulation of genes relevant for the phenotype of proliferating lymphoblasts. Interestingly, pharmacologically induced demethylation increased the efficiency of transformation of resting B cells to lymphoblastoid cells, consistent with productive cooperation between hypomethylation and lymphocyte proliferation.Conclusions: Our data provide novel clues on the role of the B cell transcription program leading to DNA methylation changes, which we find to be key to the EBV-associated conversion of resting B cells to proliferating lymphoblasts.