Francisco Joel Celio, Dai Qian, Luo Zhuojuan, Wang Yan, Chong Roxanne Hui-Heng, Tan Yee Joo, Xie Wei, Lee Guan-Huei, Lin Chengqi
Transcriptional Control in Development and Disease Laboratory, Institute of Molecular and Cell Biology, Singapore, Singapore.
Institute of Life Sciences, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China.
Mol Cell Biol. 2017 Sep 12;37(19). doi: 10.1128/MCB.00040-17. Print 2017 Oct 1.
Chronic hepatitis B virus (HBV) infection can lead to liver cirrhosis and hepatocellular carcinoma. HBV reactivation during or after chemotherapy is a potentially fatal complication for cancer patients with chronic HBV infection. Transcription of HBV is a critical intermediate step of the HBV life cycle. However, factors controlling HBV transcription remain largely unknown. Here, we found that different P-TEFb complexes are involved in the transcription of the HBV viral genome. Both BRD4 and the super elongation complex (SEC) bind to the HBV genome. The treatment of bromodomain inhibitor JQ1 stimulates HBV transcription and increases the occupancy of BRD4 on the HBV genome, suggesting the bromodomain-independent recruitment of BRD4 to the HBV genome. JQ1 also leads to the increased binding of SEC to the HBV genome, and SEC is required for JQ1-induced HBV transcription. These findings reveal a novel mechanism by which the HBV genome hijacks the host P-TEFb-containing complexes to promote its own transcription. Our findings also point out an important clinical implication, that is, the potential risk of HBV reactivation during therapy with a BRD4 inhibitor, such as JQ1 or its analogues, which are a potential treatment for acute myeloid leukemia.
慢性乙型肝炎病毒（HBV）感染可导致肝硬化和肝细胞癌。化疗期间或化疗后HBV再激活对于慢性HBV感染的癌症患者而言是一种潜在的致命并发症。HBV转录是HBV生命周期中的关键中间步骤。然而，控制HBV转录的因素在很大程度上仍不清楚。在此，我们发现不同的P-TEFb复合物参与HBV病毒基因组的转录。BRD4和超级延伸复合物（SEC）均与HBV基因组结合。溴结构域抑制剂JQ1的处理刺激HBV转录，并增加BRD4在HBV基因组上的占有率，这表明BRD4以不依赖溴结构域的方式募集到HBV基因组。JQ1还导致SEC与HBV基因组的结合增加，并且SEC是JQ1诱导的HBV转录所必需的。这些发现揭示了一种新机制，即HBV基因组劫持宿主含P-TEFb的复合物以促进其自身转录。我们的发现还指出了一个重要的临床意义，即使用BRD4抑制剂（如JQ1或其类似物，它们是急性髓性白血病的潜在治疗药物）治疗期间HBV再激活的潜在风险。
