阻止EB病毒再活化進入裂解期，有利於預防或治療EB病毒相關的疾病。我們最近發現當EB病毒進入裂解期時，病毒裂解期基因啟動子上的H3組蛋白質9號離胺酸(H3K9)的抑制型甲基化修飾減少了，這支持了過去認為表觀基因(epigenetic)調控的組蛋白質甲基化修飾可能控制著EB病毒的再活化。根據這個線索，我們推測負責移除H3K9上甲基化修飾的組蛋白質去甲基酶JMJD2，在EB病毒再活化時扮演著重要角色。本研究中，我們首先發現用小干擾RNA降低JMJD2蛋白質表現的情況下，EB病毒裂解期蛋白質的表現量會明顯減少。進一步地，用JMJD2的抑制劑ML324的處理細胞會降低EB病毒的裂解期基因表現、病毒DNA的增殖、以及病毒顆粒的產生。值得注意的是，ML324偏好阻止EB病毒 Rta蛋白質所誘導的病毒再活化，但是對另一個即早期病毒蛋白質Zta所誘導的再活化則無效。我們進而發現一些Rta調控的病毒或宿主基因，其表現量也會受到ML324的抑制。ML324也能抑制EB病毒Rta蛋白質誘發卡波西氏肉瘤皰疹病毒(另一種人類腫瘤皰疹病毒)再活化的能力，暗示JMJD2參與許多EB病毒Rta所誘導的現象之中。另一方面，我們也意外發現ML324能抑制登革病毒的感染，並且減少其病毒顆粒的產生。此抑制現象可能是透過抑制登革病毒的轉譯機制。我們的研究成果顯示以JMJD2為標的的表觀基因藥物具有潛力應用於對抗DNA與RNA病毒。

Blockage of Epstein-Barr virus (EBV) reactivation into the lytic cycle benefits prevention or therapy of EBV-associated diseases. Supporting that epigenetic histone modification may control EBV reactivation, we recently found that suppressive methylation of histone H3 lysine 9 (H3K9) on the viral lytic promoters is alleviated in the lytic state. Following this clue, we speculated that JMJD2, a histone demethylase family removing the methyl group from H3K9, plays a critical role in EBV reactivation. In this study, we first showed that induction of lytic EBV proteins was reduced upon knockdown of JMJD2. Consistently, treatment with a JMJD2 inhibitor ML324 reduced lytic gene expression, viral DNA amplification, and virion production of EBV. Notably, ML324 preferentially blocked EBV reactivation induced by a viral lytic transactivator Rta rather than another immediate-early viral protein Zta. We further identified some Rta-targeted viral and cellular genes of which induction was suppressed by ML324. ML324 also inhibited Rta-induced reactivation of another oncogenic human herpesvirus, Kaposi’s sarcoma-associated herpesvirus, suggesting that JMJD2 is involved in many Rta-regulated effects. On the other hand, we surprisingly found an inhibitory effect of ML324 on dengue virus infection and its virion production, probably at a step of viral RNA translation. Our data highlight the potential application of JMJD2-targeted epi-pharmaceuticals to both DNA and RNA viruses.

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