Binding of Epstein Barr Virus EBNA2 Unifies Multiple Sclerosis Genetic Mechanisms
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PROVIDER: PRJNA948528 | ENA |
REPOSITORIES: ENA
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Project description:Binding of Epstein Barr Virus EBNA2 Unifies Multiple Sclerosis Genetic Mechanisms
| PRJNA948529 | ENA
Project description:Epstein-Barr virus nuclear antigen 2 (EBNA2) is a transactivator of viral and cellular gene expression, which plays a critical role in the Epstein-Barr virus-associated diseases. It was reported that EBNA2 regulates gene expression by manipulating epigenetics, but the details are unclear. Recent studies showed that liquid-liquid phase separation plays an essential role in epigenetic and transcriptional regulation. Through the recently developed ATAC-see technology, we observed that EBNA2 reorganized chromatin topology to form accessible chromatin domains (ACDs) of the host genome by phase separation. The N-terminal region of EBNA2, which is necessary for phase separation, is sufficient to induce ACDs. The C-terminal domain of EBNA2 promotes the acetylation of accessible chromatin regions by recruiting histone acetylase p300 to ACDs. According to these observations, we proposed a model of EBNA2 reorganizing chromatin topology for its acetylation through phase separation to explain the mechanism of EBNA2 hijacking the host genome by controlling its epigenetics. Our findings help to understand the molecular mechanism of the EBV-associated diseases and develop therapeutics for these diseases.
2020-09-22 | GSE158288 | GEO
Project description:The Epstein-Barr virus nuclear antigen 2 (EBNA2) initiates and maintains the proliferation of infected B cells. In search of additional cellular strategies, that control EBNA2 function, we have performed a label-free mass spectrometry-based quantification of cellular proteins in EBNA2 immuno-precipitates and found polo-like kinase 1 (PLK1) to be bound to EBNA2. EBNA2/PLK1 complex formation is strongly enforced by EBNA2 S379 phosphorylation catalyzed by the mitotic CYCLIN B/CDK1 complex.
2021-08-22 | PXD022970 | Pride
Project description: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 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 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 >400 EBNA2-dependent differentially expressed human genes and >5,000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed >2,000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP-seq data revealed >1,700 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. 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.
2021-09-23 | GSE179755 | GEO
Project description: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 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 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 >400 EBNA2-dependent differentially expressed human genes and >5,000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed >2,000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP-seq data revealed >1,700 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. 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.
2021-09-23 | GSE177046 | GEO
Project description: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 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 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 >400 EBNA2-dependent differentially expressed human genes and >5,000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed >2,000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP-seq data revealed >1,700 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. 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.
2021-09-23 | GSE176232 | GEO
Project description: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 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 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 >400 EBNA2-dependent differentially expressed human genes and >5,000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed >2,000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP-seq data revealed >1,700 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. 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.
2021-09-23 | GSE178131 | GEO
Project description: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 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 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 >400 EBNA2-dependent differentially expressed human genes and >5,000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed >2,000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP-seq data revealed >1,700 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. 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.
2021-09-23 | GSE176421 | GEO
Project description:There are two major types of Epstein-Barr Virus (EBV): type 1 (EBV-1) and type 2 (EBV-2). EBV functions by manipulating gene expression in host B cells, using virus-encoded gene regulatory proteins including Epstein Barr Nuclear Antigen 2 (EBNA2). While type 1 EBNA2 is known to interact with human transcription factors (hTFs) like RBPJ, EBF1, and SPI1, type 2 EBNA2 shares only ~50% amino acid identity and may have distinct effects on the genome. In this study, we examined EBNA2 binding in EBV-1 and EBV-2 transformed human B cells to identify shared and unique EBNA2 interactions with the human genome, revealing thousands of type-specific EBNA2 ChIP-seq peaks. Our analyses revealed that both types 1 and 2 EBNA2 strongly bind to SPI1 and AP-1 motifs (BATF and JUNB). However, type 1 EBNA2 showed preferential co-occupancy with EBF1, and type 2 EBNA2 with RBPJ. These differences in b hTF co-occupancy revealed type-specific gene expression of known EBNA2 targets. Both type 1 and 2 EBNA2 binding events were highly enriched at systemic lupus erythematosus (SLE) and showed type-specific enrichment at the risk loci of multiple sclerosis (type 1) and primary biliary cholangitis (type 2). Collectively, this study reveals extensive type-specific EBNA2 interactions with the human genome, genotype-dependent binding, and distinct associations with autoimmune disorders. Our results highlight the importance of considering EBV type in disease-related investigations.
2024-03-12 | GSE246061 | GEO
Project description:There are two major types of Epstein-Barr Virus (EBV): type 1 (EBV-1) and type 2 (EBV-2). EBV functions by manipulating gene expression in host B cells, using virus-encoded gene regulatory proteins including Epstein Barr Nuclear Antigen 2 (EBNA2). While type 1 EBNA2 is known to interact with human transcription factors (hTFs) like RBPJ, EBF1, and SPI1, type 2 EBNA2 shares only ~50% amino acid identity and may have distinct effects on the genome. In this study, we examined EBNA2 binding in EBV-1 and EBV-2 transformed human B cells to identify shared and unique EBNA2 interactions with the human genome, revealing thousands of type-specific EBNA2 ChIP-seq peaks. Our analyses revealed that both types 1 and 2 EBNA2 strongly bind to SPI1 and AP-1 motifs (BATF and JUNB). However, type 1 EBNA2 showed preferential co-occupancy with EBF1, and type 2 EBNA2 with RBPJ. These differences in b hTF co-occupancy revealed type-specific gene expression of known EBNA2 targets. Both type 1 and 2 EBNA2 binding events were highly enriched at systemic lupus erythematosus (SLE) and showed type-specific enrichment at the risk loci of multiple sclerosis (type 1) and primary biliary cholangitis (type 2). Collectively, this study reveals extensive type-specific EBNA2 interactions with the human genome, genotype-dependent binding, and distinct associations with autoimmune disorders. Our results highlight the importance of considering EBV type in disease-related investigations.
2024-03-12 | GSE246060 | GEO