SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation

Yang, Hua; Mo, Jiayin; Qi, Xiaoning; Zhao, Peiyi; Song, Yunting; Yang, Ge; Wu, Jianguo; Liu, Yingle; Liu, Weiyong

doi:10.3390/v12030273

Cited by 3 publications

(1 citation statement)

References 30 publications

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“…This has been demonstrated in Herpes simplex virus (HSV-1) where loss of CTCF binding adjacent to the viral transcriptional enhancer results in reactivation of lytic gene expression [59][60][61]. Alternatively, loss of CTCF recruitment to EnhI disrupts the phased nucleosomes within the HBV enhancer region which disrupts binding of repressive transcription factors such as the Maf bZIP transcription factor F (MafF) [62] or sex determining region Y box2 (SOX2) [63]. Thirdly, it is possible that CTCF binding is important to direct nucleosome phasing at the HBV enhancer, which is important for positioning of the +1 nucleosome immediately downstream of the BCP [27].…”

Section: Discussionmentioning

confidence: 99%

CTCF regulates hepatitis B virus cccDNA chromatin topology

Dobrica,

Varghese,

Harris

et al. 2024

Journal of General Virology

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Hepatitis B Virus (HBV) is a small DNA virus that replicates via an episomal covalently closed circular DNA (cccDNA) that serves as the transcriptional template for viral mRNAs. The host protein, CCCTC-binding factor (CTCF), is a key regulator of cellular transcription by maintaining epigenetic boundaries, nucleosome phasing, stabilisation of long-range chromatin loops and directing alternative exon splicing. We previously reported that CTCF binds two conserved motifs within Enhancer I of the HBV genome and represses viral transcription, however, the underlying mechanisms were not identified. We show that CTCF depletion in cells harbouring cccDNA-like HBV molecules and in de novo infected cells resulted in an increase in spliced transcripts, which was most notable in the abundant SP1 spliced transcript. In contrast, depletion of CTCF in cell lines with integrated HBV DNA had no effect on the abundance of viral transcripts and in line with this observation there was limited evidence for CTCF binding to viral integrants, suggesting that CTCF-regulation of HBV transcription is specific to episomal cccDNA. Analysis of HBV chromatin topology by Assay for Transposase Accessible Chromatin Sequencing (ATAC-Seq) revealed an accessible region spanning Enhancers I and II and the basal core promoter (BCP). Mutating the CTCF binding sites within Enhancer I resulted in a dramatic rearrangement of chromatin accessibility where the open chromatin region was no longer detected, indicating loss of the phased nucleosome up- and down-stream of the HBV enhancer/BCP. These data demonstrate that CTCF functions to regulate HBV chromatin conformation and nucleosomal positioning in episomal maintained cccDNA, which has important consequences for HBV transcription regulation.

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Section: Discussionmentioning

confidence: 99%

CTCF regulates hepatitis B virus cccDNA chromatin topology

Dobrica,

Varghese,

Harris

et al. 2024

Journal of General Virology

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TRIM56 impairs HBV infection and replication by inhibiting HBV core promoter activity

Tian

Dong²,

Lai³

et al. 2022

Antiviral Research

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CTCF regulates hepatitis B virus cccDNA chromatin topology

Dobrica,

Varghese,

Harris

et al. 2023

Preprint

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Hepatitis B Virus (HBV) is a small DNA virus that replicates via an episomal covalently closed circular DNA (cccDNA) that serves as the transcriptional template for viral mRNAs. The host protein, CCCTC-binding factor (CTCF), is a key regulator of cellular transcription by maintaining epigenetic boundaries, nucleosome phasing, stabilisation of long-range chromatin loops and directing alternative exon splicing. We previously reported that CTCF binds two conserved motifs within Enhancer I of the HBV genome and represses viral transcripts, however, the underlying mechanisms were not identified. We show that CTCF depletion in cells harbouring cccDNA-like HBV molecules and inde novoinfected cells resulted in an increase in spliced transcripts, which was most notable in the abundant SP1 spliced transcript. In contrast, depletion of CTCF in cell lines with integrated HBV DNA had no effect on the abundance of viral transcripts and in line with this observation there was limited evidence for CTCF binding to viral integrants, suggesting that CTCF-regulation of HBV transcription is specific to episomal cccDNA. Analysis of HBV chromatin topology by Assay for Transposase Accessibility/sequencing (ATAC-Seq) revealed an accessible region spanning Enhancers I and II and the basal core promoter (BCP). Mutating the CTCF binding sites within Enhancer I resulted in a dramatic rearrangement of chromatin accessibility where the open chromatin region was no longer detected, indicating loss of the phased nucleosome up- and down-stream of the HBV enhancer/BCP. These data demonstrate that CTCF functions to regulate HBV chromatin conformation and nucleosomal positioning in episomal maintained cccDNA, which has important consequences for HBV transcription regulation.

show abstract

SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation

Cited by 3 publications

References 30 publications

CTCF regulates hepatitis B virus cccDNA chromatin topology

CTCF regulates hepatitis B virus cccDNA chromatin topology

TRIM56 impairs HBV infection and replication by inhibiting HBV core promoter activity

CTCF regulates hepatitis B virus cccDNA chromatin topology

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