To accomplish the remarkable task of lifelong infection, the Epstein-Barr virus (EBV) switches between four viral genome latency and lytic programmes to navigate the B-cell compartment and evade immune responses. The transforming programme, consisting of highly immunogenic EBV nuclear antigen (EBNA) and latent membrane proteins (LMPs), is expressed in newly infected B lymphocytes and in post-transplant lymphomas. On memory cell differentiation and in most EBV-associated Burkitt's lymphomas, all but one viral antigen are repressed for immunoevasion. To gain insights into the epigenetic mechanisms that restrict immunogenic oncoprotein expression, a genome-scale CRISPR-Cas9 screen was performed in EBV and Burkitt's lymphoma cells. Here, we show that the ubiquitin ligase ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) and its DNA methyltransferase partner DNA methyltransferase I (DNMT1) are critical for the restriction of EBNA and LMP expression. All UHRF1 reader and writer domains were necessary for silencing and DNMT3B was identified as an upstream viral genome CpG methylation initiator. Polycomb repressive complex I exerted a further layer of control over LMP expression, suggesting a second mechanism for latency programme switching. UHRF1, DNMT1 and DNMT3B are upregulated in germinal centre B cells, the Burkitt's lymphoma cell of origin, providing a molecular link between B-cell state and the EBV latency programme. These results suggest rational therapeutic targets to manipulate EBV oncoprotein expression.

中文翻译：

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DNA 甲基化酶和 PRC1 限制 B 细胞 Epstein-Barr 病毒癌蛋白的表达。


为了完成终生感染的非凡任务，EB 病毒 (EBV) 在四​​种病毒基因组潜伏和裂解程序之间切换，以导航 B 细胞区室并逃避免疫反应。该转化程序由高免疫原性 EBV 核抗原 (EBNA) 和潜伏膜蛋白 (LMP) 组成，在新感染的 B 淋巴细胞和移植后淋巴瘤中表达。在记忆细胞分化和大多数 EBV 相关伯基特淋巴瘤中，除一种病毒抗原外的所有病毒抗原都受到抑制以进行免疫逃避。为了深入了解限制免疫原性癌蛋白表达的表观遗传机制，在 EBV 和伯基特淋巴瘤细胞中进行了基因组规模的 CRISPR-Cas9 筛选。在这里，我们证明泛素连接酶泛素样 PHD 和环指结构域含有蛋白 1 (UHRF1) 及其 DNA 甲基转移酶伴侣 DNA 甲基转移酶 I (DNMT1) 对于限制 EBNA 和 LMP 表达至关重要。所有 UHRF1 读取器和写入器结构域都是沉默所必需的，并且 DNMT3B 被确定为上游病毒基因组 CpG 甲基化起始子。 Polycomb 抑制复合物 I 对 LMP 表达施加了进一步的控制，这表明了潜伏程序切换的第二种机制。 UHRF1、DNMT1 和 DNMT3B 在生发中心 B 细胞（伯基特淋巴瘤细胞起源）中上调，提供 B 细胞状态和 EBV 潜伏期程序之间的分子联系。这些结果表明操纵 EBV 癌蛋白表达的合理治疗靶点。