International Agency for Research on Cancer, World Health Organization, Lyon, France.
CIRI, Centre International de Recherche en Infectiologie (Oncogenic Herpesviruses Team), Université de Lyon, Lyon, France.
J Virol. 2019 Jun 14;93(13). doi: 10.1128/JVI.00273-19. Print 2019 Jul 1.
The histone modifier lysine (K)-specific demethylase 2B (KDM2B) plays a role in the differentiation of hematopoietic cells, and its expression appears to be deregulated in certain cancers of hematological and lymphoid origins. We have previously found that the gene is differentially methylated in cell lines derived from Epstein-Barr virus (EBV)-associated endemic Burkitt lymphoma (eBL) compared with that in EBV-negative sporadic Burkitt lymphoma-derived cells. However, whether KDM2B plays a role in eBL development has not been previously investigated. Oncogenic viruses have been shown to hijack the host cell epigenome to complete their life cycle and to promote the transformation process by perturbing cell chromatin organization. Here, we investigated whether EBV alters KDM2B levels to enable its life cycle and promote B-cell transformation. We show that infection of B cells with EBV leads to downregulation of KDM2B levels. We also show that LMP1, one of the main EBV transforming proteins, induces increased DNMT1 recruitment to the gene and augments its methylation. By altering KDM2B levels and performing chromatin immunoprecipitation in EBV-infected B cells, we show that KDM2B is recruited to the EBV gene promoters and inhibits their expression. Furthermore, forced KDM2B expression in immortalized B cells led to altered mRNA levels of some differentiation-related genes. Our data show that EBV deregulates KDM2B levels through an epigenetic mechanism and provide evidence for a role of KDM2B in regulating virus and host cell gene expression, warranting further investigations to assess the role of KDM2B in the process of EBV-mediated lymphomagenesis. In Africa, Epstein-Barr virus infection is associated with endemic Burkitt lymphoma, a pediatric cancer. The molecular events leading to its development are poorly understood compared with those leading to sporadic Burkitt lymphoma. In a previous study, by analyzing the DNA methylation changes in endemic compared with sporadic Burkitt lymphoma cell lines, we identified several differential methylated genomic positions in the proximity of genes with a potential role in cancer, and among them was the gene. encodes a histone H3 demethylase already shown to be involved in some hematological disorders. However, whether KDM2B plays a role in the development of Epstein-Barr virus-mediated lymphoma has not been investigated before. In this study, we show that Epstein-Barr virus deregulates KDM2B expression and describe the underlying mechanisms. We also reveal a role of the demethylase in controlling viral and B-cell gene expression, thus highlighting a novel interaction between the virus and the cellular epigenome.
组蛋白赖氨酸特异性去甲基酶 2B（KDM2B）在造血细胞分化中发挥作用，其表达在某些血液和淋巴来源的癌症中似乎失调。我们之前发现，与 EBV 阴性散发性 Burkitt 淋巴瘤衍生细胞相比，源自 Epstein-Barr 病毒（EBV）相关地方性 Burkitt 淋巴瘤（eBL）的细胞系中基因的差异甲基化。然而，KDM2B 是否在 eBL 发展中发挥作用尚未得到研究。致癌病毒已被证明会劫持宿主细胞表观基因组以完成其生命周期，并通过扰乱细胞染色质组织来促进转化过程。在这里，我们研究了 EBV 是否改变 KDM2B 水平以使其生命周期并促进 B 细胞转化。我们表明，EBV 感染 B 细胞会导致 KDM2B 水平下调。我们还表明，LMP1，主要的 EBV 转化蛋白之一，诱导更多的 DNMT1 募集到基因并增加其甲基化。通过改变 EBV 感染 B 细胞中的 KDM2B 水平并进行染色质免疫沉淀，我们表明 KDM2B 被募集到 EBV 基因启动子并抑制其表达。此外，在永生化 B 细胞中强制表达 KDM2B 导致一些分化相关基因的 mRNA 水平发生改变。我们的数据表明，EBV 通过表观遗传机制下调 KDM2B 水平，并为 KDM2B 在调节病毒和宿主细胞基因表达中的作用提供证据，值得进一步研究以评估 KDM2B 在 EBV 介导的淋巴瘤发生过程中的作用。在非洲，EBV 感染与地方性 Burkitt 淋巴瘤有关，这是一种儿科癌症。与导致散发性 Burkitt 淋巴瘤的分子事件相比，导致其发展的分子事件了解甚少。在之前的一项研究中，通过分析地方性与散发性 Burkitt 淋巴瘤细胞系之间的 DNA 甲基化变化，我们确定了在一些具有癌症潜在作用的基因附近的几个差异甲基化基因组位置，其中包括基因。编码已显示参与某些血液疾病的组蛋白 H3 去甲基酶。然而，KDM2B 是否在 EBV 介导的淋巴瘤的发展中发挥作用尚未研究。在这项研究中，我们表明 EBV 下调 KDM2B 的表达并描述了潜在的机制。我们还揭示了去甲基酶在控制病毒和 B 细胞基因表达中的作用，从而突出了病毒和细胞表观基因组之间的新相互作用。
