Tumor suppressor ZHX2 restricts hepatitis B virus replication via epigenetic and non-epigenetic manners

Xu, Leiqi; Wu, Zhuanchang; Tan, Siyu; Wang, Zehua; Lin, Qinghai; Li, Xiaoyan; Song, Xiaojia; Liu, Yuan; Song, Yang; Zhang, Jie; Peng, Jun; Gao, Lifen; Gong, Yaoqin; Liang, Xiaohong; Zuo, Xu; Hong, Chun Pyo

doi:10.1016/j.antiviral.2018.03.008

Cited by 25 publications

(26 citation statements)

References 30 publications

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“…To investigate the potential sensor for HBV cccDNA, we established a recombinant cccDNA (rcccDNA) cell model by transfecting prcccDNA plus pCMV‐Cre (prcccDNA/Cre) into Huh7 cells as described . This model is credited with producing high levels of rcccDNA in the hepatic nuclei, which has been proven to be a surrogate for the natural cccDNA minichromosome . As PRRs often possess two properties (physical interaction with DNA and being transcriptionally inducible by cytokines as part of a positive feedback loop to sustain innate immune responses), we treated this rcccDNA cell model with or without IFN‐α and then tested the possible sensors for cccDNA by ChIP assays.…”

Section: Resultsmentioning

confidence: 99%

“…Precursor plasmid rcccDNA (prcccDNA) and Crerecombinase expression plasmid (pCMV-Cre) were cotransfected into Huh7 cells to produce recombinant cccDNA (rcccDNA) as reported by Qi et al (15) Nuclear rcccDNA has been demonstrated to be epigenetically organized as a minichromosome and can be used as a cccDNA surrogate for HBV studies. (15)(16)(17) To investigate the effect of IFI16 overexpression on cccDNA, prcccDNA/pCMV-Cre together with FLAGtagged plasmid IFI16 (pIFI16-FLAG; Addgene, #35064) was transfected into Huh7 cells using lipofectamine 2000 (Invitrogen, Carlsbad, CA). Small interfering RNA (siRNA) specific for IFI16 (sense: 5′-UGCUGAACGCAACAGAAUCAU-3′ and antisense: 5′-AUGAUUCUGUUGCGUUCAGCA-3′) or control siRNA was transfected into Huh7 cells by HiPerFect Transfection Reagent (Qiagen, Hilden, Germany).…”

Section: Plasmid or Small Interfering Rna Transfection And Hbv Infectionmentioning

confidence: 99%

“…(15) This model is credited with producing high levels of rcccDNA in the hepatic nuclei, which has been proven to be a surrogate for the natural cccDNA minichromosome. (15)(16)(17) As PRRs often possess two properties (physical interaction with DNA and being transcriptionally inducible by cytokines as part of a positive feedback loop to sustain innate immune responses (24) ), we treated this rcccDNA cell model with or without IFN-α and then tested the possible sensors for cccDNA by ChIP assays. Results showed that IFI16, but not other possible nuclear-located innate DNA sensors (including cGAS, AIM2, and myeloid cell nuclear differentiation antigen), bound to the rcccDNA, especially after IFN-α treatment (Fig.…”

Section: Ifi16 Serves As a Unique Innate Nuclear Sensor For Hbv Cccdnamentioning

confidence: 99%

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Nuclear Sensor Interferon‐Inducible Protein 16 Inhibits the Function of Hepatitis B Virus Covalently Closed Circular DNA by Integrating Innate Immune Activation and Epigenetic Suppression

et al. 2019

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Background and Aims Nuclear‐located covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a determining factor for HBV persistence and the key obstacle for a cure of chronic hepatitis B. However, it remains unclear whether and how the host immune system senses HBV cccDNA and its biological consequences. Approach and Results Here, we demonstrated that interferon‐inducible protein 16 (IFI16) could serve as a unique innate sensor to recognize and bind to HBV cccDNA in hepatic nuclei, leading to the inhibition of cccDNA transcription and HBV replication. Mechanistically, our data showed that IFI16 promoted the epigenetic suppression of HBV cccDNA by targeting an interferon‐stimulated response element (ISRE) present in cccDNA. It is of interest that this ISRE was also revealed to play an important role in IFI16–activated type I interferon responses. Furthermore, our data revealed that HBV could down‐regulate the expression level of IFI16 in hepatocytes, and there was a negative correlation between IFI16 and HBV transcripts in liver biopsies, suggesting the possible role of IFI16 in suppressing cccDNA function under physiological conditions. Conclusions The nuclear sensor IFI16 suppresses cccDNA function by integrating innate immune activation and epigenetic regulation by targeting the ISRE of cccDNA, and IFI16 may present as a therapeutic target against HBV infection.

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Section: Resultsmentioning

confidence: 99%

Section: Plasmid or Small Interfering Rna Transfection And Hbv Infectionmentioning

confidence: 99%

Section: Ifi16 Serves As a Unique Innate Nuclear Sensor For Hbv Cccdnamentioning

confidence: 99%

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Nuclear Sensor Interferon‐Inducible Protein 16 Inhibits the Function of Hepatitis B Virus Covalently Closed Circular DNA by Integrating Innate Immune Activation and Epigenetic Suppression

et al. 2019

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“…Retinoid X Receptor α (RXRα) Enhances transcription Binds ENI, Core and S promoter [80,81] Zinc Finger and Homeoboxes 2 (ZHX2) Inhibits transcription Binds X, core and PreS2 promoter [82] a Through signal transduction STAT1 can inhibit HBV. However, HBx actively prevents its activation, limiting STAT1 s effectiveness against HBV infection.…”

Section: Protein Effect On Transcription Site Of Hbv Genome Interactimentioning

confidence: 99%

Host Transcription Factors in Hepatitis B Virus RNA Synthesis

Turton

Meier-Stephenson

Badmalia

et al. 2020

Viruses

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The hepatitis B virus (HBV) chronically infects over 250 million people worldwide and is one of the leading causes of liver cancer and hepatocellular carcinoma. HBV persistence is due in part to the highly stable HBV minichromosome or HBV covalently closed circular DNA (cccDNA) that resides in the nucleus. As HBV replication requires the help of host transcription factors to replicate, focusing on host protein–HBV genome interactions may reveal insights into new drug targets against cccDNA. The structural details on such complexes, however, remain poorly defined. In this review, the current literature regarding host transcription factors’ interactions with HBV cccDNA is discussed.

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“…HBx also increases histone acetylation and H3K4me3 and decreases HP1 binding and H3K9me3 on the cccDNA [24]. Other host transcription factors, mainly suppressors, that act via epigenetic control of HBV include SIRT3 [25], zinc finger and homeoboxes 2 (ZHX2) [26], KDM2B [27], protein arginine methyltransferase 5 (PRMT5) [28], and SETDB1 [24]. Interestingly, mutations in the basal core promoter are also reported to be associated with histone modification [29].…”

Section: Epigenetic Control Of Hbv Transcription: Histone Modificationmentioning

confidence: 99%

Epigenetic Regulation of Hepatitis B Virus Replication

Moon¹,

Kim²

2020

Chromatin and Epigenetics

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Hepatitis B virus (HBV) is the most important cause of chronic viral hepatitis worldwide. The genome of HBV is 3.2 kb partially double-stranded DNA, which is translocated to the nuclei of infected hepatocytes and converted to complete double-stranded DNA, aka covalently closed circular DNA (cccDNA). Typical course of chronic HBV infection results in inactive carrier state with clearance of viral particles in the bloodstream. However, the cccDNA can be detected in the hepatocytes from inactive carriers by sensitive methods. It has been increasingly known that epigenetic mechanisms contribute to the control of HBV replication in the inactive stage of HBV infection. Histone modification and DNA methylation have been identified in the HBV cccDNA, leading to modification of transcriptional activity. The understanding of epigenetic control of transcription will shed light on the development of new therapeutic strategy against HBV cccDNA.

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Tumor suppressor ZHX2 restricts hepatitis B virus replication via epigenetic and non-epigenetic manners

Cited by 25 publications

References 30 publications

Nuclear Sensor Interferon‐Inducible Protein 16 Inhibits the Function of Hepatitis B Virus Covalently Closed Circular DNA by Integrating Innate Immune Activation and Epigenetic Suppression

Nuclear Sensor Interferon‐Inducible Protein 16 Inhibits the Function of Hepatitis B Virus Covalently Closed Circular DNA by Integrating Innate Immune Activation and Epigenetic Suppression

Host Transcription Factors in Hepatitis B Virus RNA Synthesis

Epigenetic Regulation of Hepatitis B Virus Replication

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