SIRT7 restricts HBV transcription and replication through catalyzing desuccinylation of histone H3 associated with cccDNA minichromosome
SIRT7 restricts HBV transcription and replication through catalyzing desuccinylation of histone H3 associated with cccDNA minichromosome
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SIRT7 通过催化与 cccDNA 微型染色体相关的组蛋白 H3 的去琥珀酰化来限制 HBV 转录和复制
作者：
Yu Hai-Bo;Cheng Sheng-Tao;Ren Fang;Chen Yong;Shi Xiao-Feng;Wong Vincent Kam Wai;Law Betty Yuen Kwan;Ren Ji-Hua;Zhong Shan;Chen Wei-Xian;Xu Hong-Mei;Zhang Zhen-Zhen;Hu Jie-Li;Cai Xue-Fei;Hu Yuan;Zhang Wen-Lu;Long Quan-Xin;He Lin;Hu Zhong-Wen;Jiang Hui;Zhou
慢性乙肝病毒感染是世界范围内严重的公共卫生负担。乙肝病毒共价闭合环状DNA(CcDNA)是病毒持续存在的主要原因，也是慢性乙型肝炎(CHB)治疗的关键障碍。最近的研究表明，cccDNA的转录受组蛋白修饰，特别是组蛋白乙酰化和甲基化的表观遗传调控。在本研究中，我们通过cccDNA芯片-序列的方法，鉴定了转录活性的组蛋白琥珀酸化(H3K122ucc)是一种新的cccDNA微染色体的组蛋白修饰。沉默交配型信息调节2同系物7(SIRT7)是一种依赖NAD+的组蛋白去琥珀酰基酶，可通过与乙肝病毒核心蛋白相互作用，催化组蛋白3赖氨酸122(H3K122)去琥珀酸化而与cccDNA结合。此外，SIRT7还与组蛋白甲基转移酶、杂色抑制因子3-9同系物1(SUV39H1)和含SET结构域2(SETD2)协同作用，通过调节染色质结构来诱导乙肝病毒转录沉默。我们的研究结果加深了对ccCDNA微染色体组蛋白修饰的理解，因此cccDNA的转录沉默可能成为预防或治疗乙肝病毒感染的一种新的抗病毒策略。
Chronic hepatitis B virus (HBV) infection is a significant public health burden worldwide. HBV covalently closed circular DNA (cccDNA) organized as a minichromosome in nucleus is responsible for viral persistence and is the key obstacle for a cure of chronic hepatitis B (CHB). Recent studies suggest cccDNA transcription is epigenetically regulated by histone modifications, especially histone acetylation and methylation. In the present study, we identified transcriptionally active histone succinylation (H3K122succ) as a new histone modification on cccDNA minichromosome by using cccDNA ChIP-Seq approach. Silent mating type information regulation 2 homolog 7 (SIRT7), as an NAD+-dependent histone desuccinylase, could bind to cccDNA through interaction with HBV core protein where it catalyzed histone 3 lysine 122 (H3K122) desuccinylation. Moreover, SIRT7 acts cooperatively with histone methyltransferase, suppressor of variegation 3–9 homolog 1 (SUV39H1) and SET domain containing 2 (SETD2) to induce silencing of HBV transcription through modulation of chromatin structure. Our data improved the understanding of histone modifications of the cccDNA minichromosome, thus transcriptional silencing of cccDNA may represent a novel antiviral strategy for the prevention or treatment of HBV infection.