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 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.

Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis

2016 ◽  
Vol 22 (13) ◽  
pp. 1655-1664 ◽  
Author(s):  
Yuan Zhou ◽  
Gu Zhu ◽  
Jac C Charlesworth ◽  
Steve Simpson ◽  
Rohina Rubicz ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Risk ◽  
Epstein Barr Virus ◽  
Meta Analysis ◽  
Nuclear Antigen ◽  
Genetic Loci ◽  
Polygenic Risk ◽  
Barr Virus ◽  
Genome Wide ◽  
Epstein Barr

Background: Infection with the Epstein-Barr virus (EBV) is associated with an increased risk of multiple sclerosis (MS). Objective: We sought genetic loci influencing EBV nuclear antigen-1 (EBNA-1) IgG titers and hypothesized that they may play a role in MS risk. Methods: We performed a genome-wide association study (GWAS) of anti-EBNA-1 IgG titers in 3599 individuals from an unselected twin family cohort, followed by a meta-analysis with data from an independent EBNA-1 GWAS. We then examined the shared polygenic risk between the EBNA-1 GWAS (effective sample size ( Neff) = 5555) and a large MS GWAS ( Neff = 15,231). Results: We identified one locus of strong association within the human leukocyte antigen (HLA) region, of which the most significantly associated genotyped single nucleotide polymorphism (SNP) was rs2516049 ( p = 4.11 × 10−9). A meta-analysis including data from another EBNA-1 GWAS in a cohort of Mexican-American families confirmed that rs2516049 remained the most significantly associated SNP ( p = 3.32 × 10−20). By examining the shared polygenic risk, we show that the genetic risk for elevated anti-EBNA-1 titers is positively correlated with the development of MS, and that elevated EBNA-1 titers are not an epiphenomena secondary to MS. In the joint meta-analysis of EBNA-1 titers and MS, loci at 1p22.1, 3p24.1, 3q13.33, and 10p15.1 reached genome-wide significance ( p < 5 × 10−8). Conclusions: Our results suggest that apart from the confirmed HLA region, the association of anti-EBNA-1 IgG titer with MS risk is also mediated through non-HLA genes, and that studies aimed at identifying genetic loci influencing EBNA immune response provides a novel opportunity to identify new and characterize existing genetic risk factors for MS.

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 Notch1, Notch2, and Epstein-Barr virus–encoded nuclear antigen 2 signaling differentially affects proliferation and survival of Epstein-Barr virus–infected B cells

Blood ◽  
2009 ◽  
Vol 113 (22) ◽  
pp. 5506-5515 ◽  
Author(s):  
Hella Kohlhof ◽  
Franziska Hampel ◽  
Reinhard Hoffmann ◽  
Helmut Burtscher ◽  
Ulrich H. Weidle ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Expression Analysis ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
A Genome ◽  
Cell Immortalization ◽  
Epstein Barr

AbstractThe canonical mode of transcriptional activation by both the Epstein-Barr viral protein, Epstein-Barr virus–encoded nuclear antigen 2 (EBNA2), and an activated Notch receptor (Notch-IC) requires their recruitment to RBPJ, suggesting that EBNA2 uses the Notch pathway to achieve B-cell immortalization. To gain further insight into the biologic equivalence between Notch-IC and EBNA2, we performed a genome-wide expression analysis, revealing that Notch-IC and EBNA2 exhibit profound differences in the regulation of target genes. Whereas Notch-IC is more potent in regulating genes associated with differentiation and development, EBNA2 is more potent in inducing viral and cellular genes involved in proliferation, survival, and chemotaxis. Because both EBNA2 and Notch-IC induced the expression of cell cycle–associated genes, we analyzed whether Notch1-IC or Notch2-IC can replace EBNA2 in B-cell immortalization. Although Notch-IC could drive quiescent B cells into the cell cycle, B-cell immortalization was not maintained, partially due to an increased apoptosis rate in Notch-IC–expressing cells. Expression analysis revealed that both EBNA2 and Notch-IC induced the expression of proapoptotic genes, but only in EBNA2-expressing cells were antiapoptotic genes strongly up-regulated. These findings suggest that Notch signaling in B cells and B-cell lymphomas is only compatible with proliferation if pathways leading to antiapototic signals are active.

scholarly journals A Genome-Wide Integrative Genomic Study Localizes Genetic Factors Influencing Antibodies against Epstein-Barr Virus Nuclear Antigen 1 (EBNA-1)

PLoS Genetics ◽  
2013 ◽  
Vol 9 (1) ◽  
pp. e1003147 ◽  
Author(s):  
Rohina Rubicz ◽  
Robert Yolken ◽  
Eugene Drigalenko ◽  
Melanie A. Carless ◽  
Thomas D. Dyer ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Genetic Factors ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Factors Influencing ◽  
Genome Wide ◽  
A Genome ◽  
Genomic Study ◽  
Epstein Barr
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