SIRT7 restricts HBV transcription and replication through catalyzing desuccinylation of histone H3 associated with cccDNA minichromosome

• Published in: Clinical science (1979) Vol. 135; no. 12; pp. 1505 - 1522
• Main Authors: 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, Hong-Zhong, Huang, Ai-Long, Chen, Juan
• Format: Journal Article
• Language: English
• Published: 25.06.2021
• ISSN: 0143-5221; 1470-8736; 1470-8736
• DOI: 10.1042/CS20210392

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.