scholarly journals The Epstein-Barr Virus Episome Maneuvers between Nuclear Chromatin Compartments during Reactivation

2017 ◽  
Vol 92 (3) ◽  
Author(s):  
Stephanie A. Moquin ◽  
Sean Thomas ◽  
Sean Whalen ◽  
Alix Warburton ◽  
Samantha G. Fernandez ◽  
...  
Keyword(s):  
Human Genome ◽  
Epstein Barr Virus ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Transcription Start Sites ◽  
Barr Virus ◽  
Molecular Events ◽  
Epstein Barr ◽  
Human Side ◽  
Three Dimensional Space

ABSTRACT The human genome is structurally organized in three-dimensional space to facilitate functional partitioning of transcription. We learned that the latent episome of the human Epstein-Barr virus (EBV) preferentially associates with gene-poor chromosomes and avoids gene-rich chromosomes. Kaposi's sarcoma-associated herpesvirus behaves similarly, but human papillomavirus does not. Contacts on the EBV side localize 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. Contacts on the human side localize to gene-poor and AT-rich regions of chromatin distant from transcription start sites. Upon reactivation from latency, however, the episome moves away from repressive heterochromatin and toward active euchromatin. Our work adds three-dimensional relocalization to the molecular events that occur during reactivation. Involvement of myriad interchromosomal associations also suggests a role for this type of long-range association in gene regulation. IMPORTANCE The human genome is structurally organized in three-dimensional space, and this structure functionally affects transcriptional activity. We set out to investigate whether a double-stranded DNA virus, Epstein-Barr virus (EBV), uses mechanisms similar to those of the human genome to regulate transcription. We found that the EBV genome associates with repressive compartments of the nucleus during latency and with active compartments during reactivation. This study advances our knowledge of the EBV life cycle, adding three-dimensional relocalization as a novel component to the molecular events that occur during reactivation. Furthermore, the data add to our understanding of nuclear compartments, showing that disperse interchromosomal interactions may be important for regulating transcription.

scholarly journals The Epstein-Barr virus episome maneuvers between nuclear chromatin compartments during reactivation

2017 ◽  
Author(s):  
Stephanie A. Moquin ◽  
Sean Thomas ◽  
Sean Whalen ◽  
Alix Warburton ◽  
Samantha G. Fernanadez ◽  
...  
Keyword(s):  
Human Genome ◽  
Epstein Barr Virus ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Transcription Start Sites ◽  
Barr Virus ◽  
Molecular Events ◽  
Epstein Barr ◽  
Human Side ◽  
Three Dimensional Space

ABSTRACTThe human genome is structurally organized in three-dimensional space to facilitate functional partitioning of transcription. We learned that the latent episome of the human Epstein-Barr virus (EBV) preferentially associates with gene-poor chromosomes and avoids gene-rich chromosomes. Kaposi’s sarcoma-associated herpesvirus behaves similarly, but human papillomavirus does not. Contacts localize on the EBV side 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. Contacts localize on the human side to gene-poor regions of chromatin distant from transcription start sites. Upon reactivation from latency, however, the episome moves away from repressive heterochromatin and toward active euchromatin. Our work adds three-dimensional relocalization to the molecular events that occur during reactivation. Involvement of a myriad of interchromosomal associations also suggests a role for this type of long - range association in gene regulation.IMPORTANCEThe human genome is structurally organized in three-dimensional space, and this structure functionally affects transcriptional activity. We set out to investigate whether a double stranded DNA virus, Epstein-Barr virus (EBV), uses similar mechanisms as the human genome to regulate transcription. We found that the EBV genome associates with repressive compartments of the nucleus during latency and active compartments during reactivation. This study is advances our knowledge of the EBV life cycle, adding three-dimensional re-localization as a novel component to the molecular events that occur during reactivation. Furthermore, the data adds to our understanding of nuclear compartments, showing that disperse interchromosomal interactions may be important for regulating transcription.

scholarly journals Epstein-Barr virus nuclear antigen 2 (EBNA2) extensively rewires the human chromatin landscape at autoimmune risk loci

2020 ◽  
Author(s):  
Ted Hong ◽  
Omer Donmez ◽  
Daniel Miller ◽  
Carmy Forney ◽  
Michael Lape ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Human Genome ◽  
Genetic Risk ◽  
Epstein Barr Virus ◽  
Critical Role ◽  
Chromatin Accessibility ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Chromatin Looping ◽  
Epstein Barr

AbstractThe interplay between environmental and genetic factors plays a key role in the development of many autoimmune diseases. In particular, the Epstein-Barr virus (EBV) is an established contributor to multiple sclerosis, lupus, and other disorders. Previously, we demonstrated that the EBV nuclear antigen 2 (EBNA2) transactivating protein occupies up to half of the risk loci for a set of seven autoimmune disorders. To further examine the mechanistic roles played by EBNA2 at these loci on genome-wide scale, we globally examined gene expression, chromatin accessibility, chromatin looping, and EBNA2 binding, in a B cell line that was 1) uninfected, 2) infected with a strain of EBV lacking EBNA2, or 3) infected with a strain that expresses EBNA2. We identified >400 EBNA2-dependent differentially expressed human genes and >4,000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed >3,000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP-seq data revealed >2,000 regions where EBNA2 altered chromatin looping interactions. Importantly, autoimmune genetic risk loci were highly enriched at the sites of these EBNA2-dependent chromatin-altering events. We present examples of autoimmune risk genotype-dependent EBNA2 events, nominating genetic risk mechanisms for autoimmune risk loci such as ZMIZ1 and CD80. Taken together, our results reveal important interactions between host genetic variation and EBNA2-driven disease mechanisms. Further, our study highlights a critical role for EBNA2 in rewiring human gene regulatory programs through rearrangement of the chromatin landscape and nominates these interactions as components of genetic mechanisms that influence the risk of multiple autoimmune diseases.

scholarly journals Epstein–Barr virus nuclear antigen 2 extensively rewires the human chromatin landscape at autoimmune risk loci

2021 ◽  
Author(s):  
Ted Hong ◽  
Sreeja Parameswaran ◽  
Omer A. Donmez ◽  
Daniel Miller ◽  
Carmy Forney ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Human Genome ◽  
Genetic Risk ◽  
Epstein Barr Virus ◽  
Chromatin Accessibility ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Chromatin Looping ◽  
A Genome ◽  
Epstein Barr

The interplay between environmental and genetic factors plays a key role in the development of many autoimmune diseases. In particular, the Epstein–Barr virus (EBV) is an established contributor to multiple sclerosis, lupus, and other disorders. Previously, we showed that the EBV nuclear antigen 2 (EBNA2) transactivating protein occupies up to half of the risk loci for a set of seven autoimmune disorders. To further examine the mechanistic roles played by EBNA2 at these loci on a genome-wide scale, we globally examined gene expression, chromatin accessibility, chromatin looping, and EBNA2 binding in a B cell line that was (1) uninfected, (2) infected with a strain of EBV lacking EBNA2, or (3) infected with a strain that expresses EBNA2. We identified more than 400 EBNA2-dependent differentially expressed human genes and more than 5000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed more than 2000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP data revealed more than 1700 regions where EBNA2 altered chromatin looping interactions. Autoimmune genetic risk loci were highly enriched at the sites of these EBNA2-dependent chromatin-altering events. We present examples of autoimmune risk genotype–dependent EBNA2 events, nominating genetic risk mechanisms for autoimmune risk loci such as ZMIZ1. Taken together, our results reveal important interactions between host genetic variation and EBNA2-driven disease mechanisms. Further, our study highlights a critical role for EBNA2 in rewiring human gene regulatory programs through rearrangement of the chromatin landscape and nominates these interactions as components of genetic mechanisms that influence the risk of multiple autoimmune diseases.

scholarly journals mSphere of Influence: 3-D Culture Models Influence Studies on Epstein-Barr Virus Molecular Pathogenesis in the Epithelium

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
K. H. Y. Shair
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Epstein Barr Virus ◽  
Three Dimensional ◽  
Molecular Pathogenesis ◽  
Stratified Epithelium ◽  
Barr Virus ◽  
Efficient Replication ◽  
Culture Models ◽  
Epstein Barr

ABSTRACT Kathy Shair works in the field of Epstein-Barr virus (EBV)-associated cancers, with emphasis on nasopharyngeal carcinoma (NPC). In this mSphere of Influence article, she reflects on how the paper “Efficient replication of Epstein-Barr virus in stratified epithelium in vitro” by Temple et al. (R. M. Temple, J. Zhu, L. Budgeon, N. D. Christensen, et al., Proc Natl Acad Sci U S A 111:16544–16549, 2014, https://doi.org/10.1073/pnas.1400818111) has influenced her work on EBV molecular pathogenesis in the nasopharynx by highlighting the importance of using three-dimensional (3-D) culture models to study epithelial infection.

scholarly journals Identifying Sites Bound by Epstein-Barr Virus Nuclear Antigen 1 (EBNA1) in the Human Genome: Defining a Position-Weighted Matrix To Predict Sites Bound by EBNA1 in Viral Genomes

2009 ◽  
Vol 83 (7) ◽  
pp. 2930-2940 ◽  
Author(s):  
Lindsay R. Dresang ◽  
David T. Vereide ◽  
Bill Sugden
Keyword(s):  
Dna Binding ◽  
Human Genome ◽  
Binding Sites ◽  
Epstein Barr Virus ◽  
Consensus Sequence ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Dna Binding Sites ◽  
Weighted Matrix ◽  
Epstein Barr

ABSTRACT We identified binding sites for Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) in the human genome using chromatin immunoprecipitation and microarrays. The sequences for these newly identified sites were used to generate a position-weighted matrix (PWM) for EBNA1's DNA-binding sites. This PWM helped identify additional DNA-binding sites for EBNA1 in the genomes of EBV, Kaposi's sarcoma-associated herpesvirus, and cercopithecine herpesvirus 15 (CeHV-15) (also called herpesvirus papio 15). In particular, a homologue of the Rep* locus in EBV was predicted in the genome of CeHV-15, which is notable because Rep* of EBV was not predicted by the previously developed consensus sequence for EBNA1's binding DNA. The Rep* of CeHV-15 functions as an origin of DNA synthesis in the EBV-positive cell line Raji; this finding thus builds on a set of DNA-binding sites for EBNA1 predicted in silico.

scholarly journals Three-dimensional structure of the Epstein–Barr virus capsid

2012 ◽  
Vol 93 (8) ◽  
pp. 1769-1773 ◽  
Author(s):  
Raphaele Germi ◽  
Gregory Effantin ◽  
Laurence Grossi ◽  
Rob W. H. Ruigrok ◽  
Patrice Morand ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Structural Information ◽  
Gradient Centrifugation ◽  
Three Dimensional ◽  
Human Herpesvirus ◽  
Sucrose Density Gradient ◽  
Dimensional Structure ◽  
Sucrose Density Gradient Centrifugation ◽  
Barr Virus ◽  
Epstein Barr

Epstein–Barr virus (EBV), a gammaherpesvirus, infects >90 % of the world’s population. Primary infection by EBV can lead to infectious mononucleosis, and EBV persistence is associated with several malignancies. Despite its importance for human health, little structural information is available on EBV. Here we report the purification of the EBV capsid by CsCl- or sucrose density-gradient centrifugation. Cryo-electron microscopy and image analysis resulted in two slightly different three-dimensional structures at about 20 Å resolution. These structures were compared with that of human herpesvirus 8, another gammaherpesvirus. CsCl-gradient purification leads to the removal of part of the triplex complex around the fivefold axes, whereas the complexes between hexons remained in place. This may be due to local differences in stability resulting from variation in quasi-equivalent interactions between pentons and hexons compared with those between hexons only.

scholarly journals Epstein-Barr Virus Episome Physically Interacts with Active Regions of the Host Genome in Lymphoblastoid Cells

2020 ◽  
Vol 94 (24) ◽  
Author(s):  
Luopin Wang ◽  
Jun Laing ◽  
Bingyu Yan ◽  
Hufeng Zhou ◽  
Liangru Ke ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Growth ◽  
Human Genome ◽  
Epstein Barr Virus ◽  
Active Regions ◽  
Host Genome ◽  
Lymphoblastoid Cells ◽  
Barr Virus ◽  
Interphase Cells ◽  
Epstein Barr

ABSTRACT The Epstein-Barr virus (EBV) episome is known to interact with the three-dimensional structure of the human genome in infected cells. However, the exact locations of these interactions and their potential functional consequences remain unclear. Recently, high-resolution chromatin conformation 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 a 10-kb resolution, we have identified 15,000 reproducible contacts between EBV episome(s) and the human genome. These contacts are highly enriched in chromatin regions denoted by typical or super enhancers and active markers, including histone H3K27ac and H3K4me1. 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 2-fold enrichment in host regions bound by EBV nuclear antigen 2 (EBNA2) and EBNA3 transcription factors. Circular chromosome conformation capture followed by sequencing (4C-seq) using the EBV origin of plasmid replication (oriP) as a “bait” in lymphoblastoid cells further confirmed contacts with active chromatin regions. Collectively, our analysis supports interactions between EBV episome(s) and active regions of the human genome in lymphoblastoid cells. IMPORTANCE EBV is associated with ∼200,000 cancers each year. In vitro, EBV can transform primary human B lymphocytes into immortalized cell lines. EBV-encoded proteins, along with noncoding RNAs and microRNAs, hijack cellular proteins and pathways to control cell growth. EBV nuclear proteins usurp normal transcriptional programs to activate the expression of key oncogenes, including MYC, to provide a proliferation signal. EBV nuclear antigens also repress CDKN2A to suppress senescence. EBV membrane protein activates NF-κB to provide survival signals. EBV genomes are maintained by EBNA1, which tethers EBV episomes to the host chromosomes during mitosis. However, little is known about where EBV episomes are located in interphase cells. In interphase cells, EBV promoters drive the expression of latency genes, while oriP functions as an enhancer for these promoters. In this study, integrative analyses of published lymphoblastoid cell line (LCL) Hi-C data and our 4C-seq experiments position EBV episomes to host genomes with active epigenetic marks. These contact points were significantly enriched for super enhancers. The close proximity of EBV episomes and the super enhancers that are enriched for transcription cofactors or mediators in lymphoblasts may benefit EBV gene expression, suggesting a novel mechanism of transcriptional activation.

Sign in / Sign up

Export Citation Format

Share Document