Epstein-Barr (EB)病毒以潛伏(latent)且無病症的狀態終生感染全球超過90%的人口，然而病毒由潛伏感染再活化進入裂解(lytic)感染時，常伴隨發生包括癌症在內的疾病。過去文獻指出：人類B細胞中的組蛋白甲基轉移酶(histone methyltransferases)可透過表基因體(epigenetic)調控的方式抑制EB病毒裂解期基因的表現，藉此維持病毒潛伏感染。然而一旦EB病毒發生再活化，它要如何抵抗細胞內表基因體抑制的狀態，目前還不清楚。本研究中，我們發現當EB病毒再活化時，細胞中有一些組蛋白甲基轉移酶的表現明顯下降，其中一種H3K9組蛋白甲基轉移酶(suppressor of variegation 3-9 homolog 1, SUV39H1)的表現會被EB病毒裂解期轉活化因子Rta所抑制。蛋白酶體(proteosome)抑制劑MG132會阻止Rta對SUV39H1蛋白質表現的抑制，說明蛋白酶體降解參與在此機制當中。當大量表現SUV39H1或以MG132回復SUV39H1表現時，Rta啟動病毒裂解期基因表現的情形會明顯降低，暗示降解SUV39H1對於Rta有效率地促進病毒再活化是重要的。為了探究Rta對表基因體調控的影響，我們以CRISPR/Cas9技術製造剔除Rta基因的重組EB病毒，並發展選殖單株重組病毒的策略。本研究將揭露EB病毒再活化時主動影響表基因體調控的獨特角色，有助於釐清表基因體調控策略應用於治療EB病毒相關疾病的潛力。

Epstein-Barr virus (EBV) establishes life-long latent infection in more than 90% of human population without symptom, while viral reactivation into the lytic cycle is associated with some diseases including cancers. Previous studies revealed that cellular histone methyltransferases (HMTs) maintain EBV latency in B cells through epigenetic repression of viral lytic gene expression. Nevertheless, upon EBV reactivation, how the virus counteracts the epigenetic repression state remains unclear. In this study we found that the viral lytic infection was associated with reduction of several histone methyltransferases, and that suppressor of variegation 3-9 homolog 1 (SUV39H1), a methyltransferase of histone H3 lysine 9, was downregulated by ectopic expression of a viral lytic transactivator Rta. The Rta-mediated SUV39H1 downregulation was impeded by treatment with a proteosome inhibitor MG132, indicating that the underlying mechanism involves proteasomal degradation. Meanwhile, Rta-induced viral lytic gene expression was significantly reduced when SUV39H1 was overexpressed or recovered by MG132 treatment, suggesting that downregulation of SUV39H1 is important for efficient Rta-driven EBV reactivation. To further investigate the effects of Rta on epigenetic regulation, we generated recombinant Rta-knockout EBV by using a modified clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) system, and have developed a strategy to isolate the recombinant viral clones with expected gene modification. This study will identify a novel active role of EBV in epigenetic control during viral reactivation, shedding light on the therapeutic potential of epigenetic intervention for EBV-associated diseases.

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