The three-dimensional structure of Epstein-Barr virus genome varies by latency type and is regulated by PARP1 enzymatic activity
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ABSTRACT:
ORGANISM(S): human gammaherpesvirus 4 Homo sapiens
PROVIDER: GSE159837 | GEO | 2021/11/16
REPOSITORIES: GEO
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Project description:Epstein-Barr virus (EBV) establishes life-long latency in human B-cells by maintaining its chromatinized episomes within the nucleus. These circularized mini-chromosomes do not integrate into the host genome. Therefore, it is essential for EBV to organize its chromatin in a manner suitable for genomic stability, DNA replication, and efficient gene expression. Poly [ADP-ribose] polymerase 1 (PARP1) activity is significantly higher in B-cells infected with EBV than those without, and considerably higher in the transcriptionally active type III latency compared to the immunoevasive type I. In addition to its role in DNA damage response, PARP1 has been implicated in transcriptional regulation and structural maintenance of both the human and EBV genome at specific regions. To better understand PARP1's role in the regulation of the EBV episome, we have functionally characterized the effect of PARP enzymatic inhibition on total episomal structure through in situ Hi-C mapping, generating the first complete 3D structure of the EBV genome. We have also mapped intragenomic contact changes after PARP inhibition to global binding of the chromatin looping factors CTCF and cohesin across the EBV genome. Additionally, PARP inhibition was shown to alter gene expression at the regions where chromatin looping was most effected. Finally, we have identified a novel function of PARP, which regulates cohesin complex chromatin binding. In conclusion, PARP1 inhibition does not alter the location of cohesin binding but does increase its frequency of binding at these regions. Despite this, there are fewer overall unique intragenomic interactions after PARP inhibition, while some areas have new chromatin loops not seen in the untreated EBV episome, leading us to conclude that PARP does have an essential role in the regulation of global EBV chromatin structure. The altered expression profile after the structural rearrangement induced by PARP inhibition also supports the idea that PARP1 helps maintain EBV latency programs.
2021-11-05 | GSE160973 | GEO
Project description:PARP does have an essential role in the regulation of global EBV episome chromatin structure. We have functionally characterized the effect of PARP enzymatic inhibition on total episomal structure and we mapped intragenomic contact changes after PARP inhibition to global binding of the chromatin looping factors CTCF and cohesin across the EBV genome. The altered expression profile after the structural rearrangement induced by PARP inhibition supports the model where PARP1 helps maintain EBV latency programs.
2021-11-16 | GSE159834 | GEO
Project description:PARP does have an essential role in the regulation of global EBV episome chromatin structure. We have functionally characterized the effect of PARP enzymatic inhibition on total episomal structure and we mapped intragenomic contact changes after PARP inhibition to global binding of the chromatin looping factors CTCF and cohesin across the EBV genome. The altered expression profile after the structural rearrangement induced by PARP inhibition supports the model where PARP1 helps maintain EBV latency programs.
2021-11-16 | GSE159836 | GEO
Project description:Epstein Barr virus (EBV) is a potentially oncogenic gammaherpesvirus that establishes a chronic, latent infection in memory B cells. The EBV genome persists in infected host cells as a chromatinized episome and is subject to chromatin-mediated regulation. Binding of the host insulator protein CTCF to the EBV genome has an established role in maintaining viral latency type. CTCF is posttranslationally modified by the host enzyme PARP1. PARP1, or poly(ADP-ribose) polymerase 1, catalyzes the transfer of a poly(ADP-ribose) (PAR) moiety from NAD+ onto acceptor proteins, including itself, histone proteins, and CTCF. PARylation of CTCF by PARP1 can affect CTCF's insulator activity, DNA binding capacity, and ability to form chromatin loops. Both PARP1 and CTCF have been implicated in the regulation of EBV latency and lytic reactivation. Thus, we predicted that pharmacological inhibition with PARP1 inhibitors would affect EBV latency type through a chromatin-specific mechanism. Here, we show that PARP1 and CTCF colocalize at specific sites throughout the EBV genome and provide evidence to suggest that PARP1 acts to stabilize CTCF binding and maintain the open chromatin landscape at the active Cp promoter during type III latency. Further, PARP1 activity is important in maintaining latency type-specific viral gene expression. The data presented here provide a rationale for the use of PARP inhibitors in the treatment of EBV-associated cancers exhibiting type III latency and ultimately could contribute to an EBV-specific treatment strategy for AIDS-related or posttransplant lymphomas.IMPORTANCE EBV is a human gammaherpesvirus that infects more than 95% of individuals worldwide. Upon infection, EBV circularizes as an episome and establishes a chronic, latent infection in B cells. In doing so, the virus utilizes host cell machinery to regulate and maintain the viral genome. In otherwise healthy individuals, EBV infection is typically nonpathological; however, latent infection is potentially oncogenic and is responsible for 1% of human cancers. During latent infection, EBV expresses specific sets of proteins according to the given latency type, each of which is associated with specific types of cancers. For example, type III latency, in which the virus expresses its full repertoire of latent proteins, is characteristic of AIDS-associated and posttransplant lymphomas associated with EBV infection. Understanding how viral latency type is regulated at the chromatin level may reveal potential targets for EBV-specific pharmacological intervention in EBV-associated cancers.
| S-EPMC6146685 | biostudies-literature
Project description:The three-dimensional structure of Epstein-Barr virus genome varies by latency type and is regulated by PARP1 enzymatic activity
| PRJNA670903 | ENA
Project description:The three-dimensional structure of Epstein-Barr virus genome varies by latency type and is regulated by PARP1 enzymatic activity
| PRJNA675024 | ENA
Project description:Epstein Barr Virus (EBV) is a potentially oncogenic gammaherpesvirus that establishes a chronic, latent infection in memory B cells. The EBV genome persists in infected host cells as a chromatinized episome and is subject to chromatin-mediated regulation. Binding of the host insulator protein CTCF to the EBV genome has an established role in maintaining viral latency type. CTCF is post-translationally modified by the host enzyme PARP1. PARP1, or Poly(ADP-ribose) polymerase 1, catalyzes the transfer of a poly(ADP-ribose) (PAR) moiety from NAD+ onto acceptor proteins including itself, histone proteins, and CTCF. PARylation of CTCF by PARP1 can affect CTCF’s insulator activity, DNA binding capacity, and ability to form chromatin loops. Both PARP1 and CTCF have been implicated in the regulation of EBV latency and lytic reactivation. Thus, we predicted that pharmacological inhibition with PARP1 inhibitors would affect EBV latency type through a chromatin-specific mechanism. Here, we show that PARP1 and CTCF colocalize at specific sites throughout the EBV genome, and provide evidence to suggest that PARP1 acts to stabilize CTCF binding and maintain the open chromatin landscape at the active Cp promoter during type III latency. Further, PARP1 activity is important in maintaining latency type-specific viral gene expression. The data presented here provide a rationale for the use of PARP inhibitors in the treatment of EBV-associated cancers exhibiting type III latency, and could ultimately contribute to an EBV-specific treatment strategy for AIDS-related or post-transplant lymphomas.
2018-06-27 | GSE115829 | GEO
Project description:The three-dimensional structure of Epstein-Barr virus genome varies by latency type and is regulated by PARP1 enzymatic activity [ChIP-Seq]
| PRJNA670905 | ENA
Project description:The three-dimensional structure of Epstein-Barr virus genome varies by latency type and is regulated by PARP1 enzymatic activity [RNA-Seq]
| PRJNA670904 | ENA
Project description:Epstein-Barr virus (EBV) escapes host immunity by the reversible and epigenetic silencing of immunogenic viral genes. We previously presented evidence that a dynamic chromatin domain, which we have referred to as the latency control region (LCR), contributes to the reversible repression of EBNA2 and LMP1 gene transcription. We now explore the protein-DNA interaction profiles for a few known regulatory factors and histone modifications that regulate LCR structure and activity. A chromatin immunoprecipitation assay combined with real-time PCR analysis was used to analyze protein-DNA interactions at approximately 500-bp intervals across the first 60,000 bp of the EBV genome. We compared the binding patterns of EBNA1 with those of the origin recognition complex protein ORC2, the chromatin boundary factor CTCF, the linker histone H1, and several histone modifications. We analyzed three EBV-positive cell lines (MutuI, Raji, and LCL3459) with distinct transcription patterns reflecting different latency types. Our findings suggest that histone modification patterns within the LCR are complex but reflect differences in each latency type. The most striking finding was the identification of CTCF sites immediately upstream of the Qp, Cp, and EBER transcription initiation regions in all three cell types. In transient assays, CTCF facilitated EBNA1-dependent transcription activation of Cp, suggesting that CTCF coordinates interactions between different chromatin domains. We also found that histone H3 methyl K4 clustered with CTCF and EBNA1 at sites of active transcription or DNA replication initiation. Our findings support a model where CTCF delineates multiple domains within the LCR and regulates interactions between these domains that correlate with changes in gene expression.
| S-EPMC1900095 | biostudies-literature