Global alternative RNA splicing and mRNA expression analysis of Epstein-Barr Virus EBNA2-regulated cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE165616 | GEO | 2022/12/30
REPOSITORIES: GEO
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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 | 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 | 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 | GSE176421 | 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:Gene expression programs depend on sequence-specific DNA binding transcription factors, but the mechanisms that control the selective binding of these factors in a chromosomal and genomic context remain enigmatic. Here, we show that two master regulators of B-cell fate, namely EBF1 and RBP-jk, show variable genome-wide chromosome distribution in two related B-lymphocyte lines carrying different forms of Epstein-Barr Virus (EBV) latency. The latency-type specific EBV-encoded EBNA2 colocalized with RBP-jk and EBF1 at induced binding sites. Colocalization of EBF1, RBP-jk, and EBNA2 correlated with transcriptional activation. Conditional expression or repression of EBNA2 lead to a rapid alteration in RBP-jk and EBF1 binding. Biochemical and shRNA depletion studies provide evidence for cooperative assembly at co-occupied sites. These findings reveal that non-DNA binding cofactors can facilitate combinatorial interactions to induce new patterns of transcription factor occupancy and gene programming Examination of EBNA2/EBF1/EBP-jk binding in MutuI and LCL cell lines
2015-12-16 | E-GEOD-75503 | biostudies-arrayexpress
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 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:Gene expression programs depend on sequence-specific DNA binding transcription factors, but the mechanisms that control the selective binding of these factors in a chromosomal and genomic context remain enigmatic. Here, we show that two master regulators of B-cell fate, namely EBF1 and RBP-jk, show variable genome-wide chromosome distribution in two related B-lymphocyte lines carrying different forms of Epstein-Barr Virus (EBV) latency. The latency-type specific EBV-encoded EBNA2 colocalized with RBP-jk and EBF1 at induced binding sites. Colocalization of EBF1, RBP-jk, and EBNA2 correlated with transcriptional activation. Conditional expression or repression of EBNA2 lead to a rapid alteration in RBP-jk and EBF1 binding. Biochemical and shRNA depletion studies provide evidence for cooperative assembly at co-occupied sites. These findings reveal that non-DNA binding cofactors can facilitate combinatorial interactions to induce new patterns of transcription factor occupancy and gene programming
2015-12-16 | GSE75503 | GEO
Project description:Gene expression programs depend on sequence-specific DNA binding transcription factors, but the mechanisms that control the selective binding of these factors in a chromosomal and genomic context remain enigmatic. Here, we show that two master regulators of B-cell fate, namely EBF1 and RBP-jk, show variable genome-wide chromosome distribution in two related B-lymphocyte lines carrying different forms of Epstein-Barr Virus (EBV) latency. The latency-type specific EBV-encoded EBNA2 colocalized with RBP-jk and EBF1 at induced binding sites. Colocalization of EBF1, RBP-jk, and EBNA2 correlated with transcriptional activation. Conditional expression or repression of EBNA2 lead to a rapid alteration in RBP-jk and EBF1 binding. Biochemical and shRNA depletion studies provide evidence for cooperative assembly at co-occupied sites. These findings reveal that non-DNA binding cofactors can facilitate combinatorial interactions to induce new patterns of transcription factor occupancy and gene programming
2015-12-16 | GSE75385 | GEO