The three-dimensional structure of Epstein-Barr virus genome varies by latency type and is regulated by PARP1 enzymatic activity [ChIP-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): human gammaherpesvirus 4
PROVIDER: GSE159834 | GEO | 2021/11/16
REPOSITORIES: GEO
Similar Datasets
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) 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: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:Our group has previously identified how PARP1 can control EBV latency by: (1) altering the 3D virus chromatin structure [28]; (2) regulating CTCF binding on EBV promoters and supporting the latency expression program [29-32]; (3) repressing the lytic gene expression by binding BZLF1 promoter [33, 34]. To date, the therapeutic effect of PARP1 inhibitors on EBV+ lymphomagenesis has been poorly explored. Therefore, we aimed to investigate whether PARP1i was able to counteract EBV-driven tumors in a LCL xenograft model and identify, and confirm, possible mechanisms underlying its therapeutic effect. In the present study we demonstrate that PARP1 inhibition restricts EBV-driven lymphoma in vivo, pointing out the oncogene MYC as its functional target. Specifically, PARP1 inhibition reverts the tumor growth and the metastatic potential of EBV+ LCL, inducing a dramatic transcriptional reprogramming. Interestingly, the absence of PARP1 activity causes a decrease in MYC expression, subsequently leading to a dysregulation of MYC-associated co-factors and targets, both in vivo and in vitro. Our findings also corroborate the link between PARP1 and EBNA2 expression, that we previously demonstrated in vitro. Overall, our study strengthens the central role of PARP1 in EBV malignant transformation and outlines the EBNA2/MYC pathway as an additional target of PARP1 regulation in LCL
2024-06-27 | GSE236050 | GEO
Project description:Epstein-Barr virus (EBV) episome is known to interact with the three-dimensional structure of human genome in infected cells. However, the exact locations of these interactions and their potential functional consequences remain unclear. Recently the high-resolution chromatin interaction capture (Hi-C) assays in lymphoblastoid cells have become available enabling us to precisely map the contacts between the EBV episome(s) and the human host genome. Using available Hi-C data at 10kb resolution, we have identified nearly 15000 reproducible contacts between EBV episome and human genome. These contacts are highly enriched in chromatin regions denoted by typical or super enhancers and active marks including histone H3 K27ac, K4me1, K79me2 and K4me2. Additionally, these contacts are highly enriched at loci bound by host transcription factors that regulate B cell growth (e.g. IKZF1 and RUNX3), factors that enhance cell proliferation (e.g. HDGF) or factors that promote viral replication (e.g. NBS1 and NFIC). EBV contacts show nearly two-fold enrichment in host regions bound by EBV EBNA2 and EBNA3B transcription factors. Chromosome conformation capture coupled with sequencing (4C-seq) using the EBV oriP as a “bait” loci in lymphoblastoid cells further confirmed contact with active chromatin regions. Collectively, our analysis supports the interaction between EBV episome(s) and active regions of human genome in lymphoblastoid cells.
2020-09-23 | GSE154052 | GEO
Project description:Reward-related memory is an important factor in cocaine seeking. One necessary signaling mechanism for long-term memory formation is the activation of poly(ADP-ribose) polymerase-1 (PARP-1), via poly(ADP-ribosyl)ation. We demonstrate herein that auto-poly(ADP-ribosyl)ation of activated PARP-1 was significantly pronounced during retrieval of cocaine-associated contextual memory, in the central amygdala (CeA) of rats expressing cocaine-conditioned place preference (CPP). Intra-CeA pharmacological and shRNA depletion of PARP-1 activity during cocaine-associated memory retrieval abolished CPP. In contrast, PARP-1 inhibition after memory retrieval did not affect CPP reconsolidation process and subsequent retrievals. Chromatin Immuoprecipitation (ChIP) sequencing revealed that PARP-1 binding in the CeA is highly enriched in genes involved in neuronal signaling. We identified amongst PARP targets in CeA a single gene, yet uncharacterized and encoding a putative transposase inhibitor, at which PARP-1 enrichment dramatically increases during cocaine-associated memory retrieval and positively correlates with CPP. Our findings have important implications for understanding drug-related behaviors, and suggest possible future therapeutic targets for drug abuse. 4 samples, each is pooled central amygdalae tissues collected from 2 rats. Rats were trained for cocaine-conditioned place-preference (CPP), tissues were harvested immediately following cocaine-CPP retrieval. Three groups of rats were used: high cocaine CPP, low cocaine CPP and control saline only trained rats.
2016-06-25 | E-GEOD-83718 | biostudies-arrayexpress
Project description:Reward-related memory is an important factor in cocaine seeking. One necessary signaling mechanism for long-term memory formation is the activation of poly(ADP-ribose) polymerase-1 (PARP-1), via poly(ADP-ribosyl)ation. We demonstrate herein that auto-poly(ADP-ribosyl)ation of activated PARP-1 was significantly pronounced during retrieval of cocaine-associated contextual memory, in the central amygdala (CeA) of rats expressing cocaine-conditioned place preference (CPP). Intra-CeA pharmacological and shRNA depletion of PARP-1 activity during cocaine-associated memory retrieval abolished CPP. In contrast, PARP-1 inhibition after memory retrieval did not affect CPP reconsolidation process and subsequent retrievals. Chromatin Immuoprecipitation (ChIP) sequencing revealed that PARP-1 binding in the CeA is highly enriched in genes involved in neuronal signaling. We identified amongst PARP targets in CeA a single gene, yet uncharacterized and encoding a putative transposase inhibitor, at which PARP-1 enrichment dramatically increases during cocaine-associated memory retrieval and positively correlates with CPP. Our findings have important implications for understanding drug-related behaviors, and suggest possible future therapeutic targets for drug abuse.
2016-06-25 | GSE83718 | GEO
Project description:Using chromatin conformation capture methods, we learned that the latent episome of the human Epstein-Barr virus (EBV) displays preferential chromosome association that correlates with gene density. The episome avoids gene-rich chromosomes and favors gene-poor chromosomes. Kaposi’s sarcoma-associated herpesvirus behaves similarly, but human papillomavirus does not, suggesting limited evolutionary conservation of this strategy. Moreover, the strongest contacts we detected between the human genome and EBV episome localized to OriP, the latent origin of replication. This genetic element, and the EBNA1 protein that binds there, are sufficient to reconstitute chromosome association preferences of the entire episome. Upon reactivation from latency, however, these preferences are lost. Detailed mapping of changes in interchromosomal contacts reveal that the episome moves away from repressive heterochromatin and toward activating euchromatin. Our work adds three-dimensional relocalization to the molecular events that occur during the genetic switch from EBV latency to reactivation. The involvement of only a myriad of interchromosomal contacts also argues for a possible role of this type of long-range association in gene regulation.
2017-11-13 | GSE98120 | GEO
Project description:Using chromatin conformation capture methods, we learned that the latent episome of the human Epstein-Barr virus (EBV) displays preferential chromosome association that correlates with gene density. The episome avoids gene-rich chromosomes and favors gene-poor chromosomes. Kaposi’s sarcoma-associated herpesvirus behaves similarly, but human papillomavirus does not, suggesting limited evolutionary conservation of this strategy. Moreover, the strongest contacts we detected between the human genome and EBV episome localized to OriP, the latent origin of replication. This genetic element, and the EBNA1 protein that binds there, are sufficient to reconstitute chromosome association preferences of the entire episome. Upon reactivation from latency, however, these preferences are lost. Detailed mapping of changes in interchromosomal contacts reveal that the episome moves away from repressive heterochromatin and toward activating euchromatin. Our work adds three-dimensional relocalization to the molecular events that occur during the genetic switch from EBV latency to reactivation. The involvement of only a myriad of interchromosomal contacts also argues for a possible role of this type of long-range association in gene regulation.
2017-11-13 | GSE98122 | GEO
Project description:Using chromatin conformation capture methods, we learned that the latent episome of the human Epstein-Barr virus (EBV) displays preferential chromosome association that correlates with gene density. The episome avoids gene-rich chromosomes and favors gene-poor chromosomes. Kaposi’s sarcoma-associated herpesvirus behaves similarly, but human papillomavirus does not, suggesting limited evolutionary conservation of this strategy. Moreover, the strongest contacts we detected between the human genome and EBV episome localized to OriP, the latent origin of replication. This genetic element, and the EBNA1 protein that binds there, are sufficient to reconstitute chromosome association preferences of the entire episome. Upon reactivation from latency, however, these preferences are lost. Detailed mapping of changes in interchromosomal contacts reveal that the episome moves away from repressive heterochromatin and toward activating euchromatin. Our work adds three-dimensional relocalization to the molecular events that occur during the genetic switch from EBV latency to reactivation. The involvement of only a myriad of interchromosomal contacts also argues for a possible role of this type of long-range association in gene regulation.
2017-11-13 | GSE98121 | GEO