Chromatin binding protein HMGN1 promotes HBV cccDNA transcription and replication by regulating the phosphorylation of histone 3

作者全名："Tan, Ming; Liu, Yuting; Dong, Meiling; Cheng, Shengtao; Ren, Jihua; Zhang, Hui; Chen, Wanjin; Li, Dian; Gao, Tingting; Chen, Juan; Zhang, Zhenzhen"

作者地址："[Tan, Ming; Zhang, Zhenzhen] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Chongqing Key Lab Child Infect & Immun, Natl Clin Res Ctr Child Hlth & Disorders,Childrens, Chongqing, Peoples R China; [Tan, Ming; Liu, Yuting; Cheng, Shengtao; Ren, Jihua; Zhang, Hui; Li, Dian; Gao, Tingting; Chen, Juan] Chongqing Med Univ, Key Lab Mol Biol Infect Dis Designated, Chinese Minist Educ, Chongqing, Peoples R China; [Dong, Meiling] Nanchang Univ, Dept Clin Lab, Infect Dis Hosp, Nanchang, Peoples R China; [Chen, Wanjin; Chen, Juan] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing, Peoples R China; [Zhang, Zhenzhen] Chongqing Med Univ, Childrens Hosp, Dept Neurol, 136 Zhongshan Second Rd, Chongqing 400014, Peoples R China; [Chen, Juan] Coll Life Sci Bldg, Room 617,1 Yixue yuan Rd, Chongqing 400016, Peoples R China"

通信作者："Zhang, ZZ (通讯作者)，Chongqing Med Univ, Childrens Hosp, Dept Neurol, 136 Zhongshan Second Rd, Chongqing 400014, Peoples R China.; Chen, J (通讯作者)，Coll Life Sci Bldg, Room 617,1 Yixue yuan Rd, Chongqing 400016, Peoples R China."

来源：ANTIVIRAL RESEARCH

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001153404500001

JCR分区：Q1

影响因子：7.6

年份：2024

卷号：221

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：HMGN1; cccDNA; Histone; CLK2

摘要："Background and aims: Direct elimination of cccDNA remains a formidable obstacle due to the persistent and stable presence of cccDNA in hepatocyte nuclei. The silencing of cccDNA transcription enduringly is one of alternative strategies in the treatment of hepatitis B. Protein binding to cccDNA plays an important role in its transcriptional regulation; thus, the identification of key factors involved in this process is of great importance. Approaches and results: In the present study, high mobility group nucleosome binding domain 1 (HMGN1) was screened out based on our biotin-avidin enrichment system. First, chromatin immunoprecipitation and fluorescent in situ hybridization assays confirmed the binding of HMGN1 with cccDNA in the nucleus. Second, functional experiments in HBV-infected cells showed that the promoting effect of HMGN1 on HBV transcription and replication depended on the functional region of the nucleosomal binding domain, while transfection of the HMGN1 mutant showed no influence on HBV compared with the vector. Third, further mechanistic exploration revealed that the silencing of HMGN1 increased the level of phosphorylase CLK2 and promoted H3 phosphorylation causing the reduced accessibility of cccDNA. Moreover, silenced HMGN1 was mimicked in HBV (r) cccDNA mouse model of HBV infection in vivo. The results showed that silencing HMGN1 inhibited HBV replication in vivo. Conclusions: In summary, our study identified that a host protein can bind to cccDNA and promote its transcription, providing a candidate strategy for anti-HBV targeting to interfere with the transcriptional activity of cccDNA microchromosomes."

基金机构："Key Technologies RD Program [2022YFA1303600]; National Natural Science Foundation of China [U23A20472, 82273423, 82202501]; Scientific and Technological Research Program of Chongqing Municipal Education Commission [KJQN202300465]; Chongqing Natural Science"

基金资助正文："<STRONG> </STRONG>This work was supported by the Key Technologies R & D Program (2022YFA1303600 to JC) ; National Natural Science Foundation of China (U23A20472 and 82273423 to JC, 82202501 to STC) ; Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJQN202300465 to STC) ; Chongqing Natural Science"