Cellular factors associated with latency and spontaneous Epstein–Barr virus reactivation in B-lymphoblastoid cell lines

Davies, Michael L.; Xu, Shisan; Lyons‐Weiler, James; Rosendorff, Adam; Webber, Steven A.; Wasil, Laura R.; Metes, Diana; Rowe, David

doi:10.1016/j.virol.2010.01.002

Cited by 35 publications

(41 citation statements)

References 84 publications

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“…The MEF2B level was found to be elevated in several B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL), which may be commonly infected by EBV (31,32). EBF1 was identified as a B-cell identity factor important for maintaining EBV latency (45). EBF1 was also found to occupy many of the EBNA2 chromosome binding sites (8).…”

Section: Discussionmentioning

confidence: 99%

Identification of MEF2B , EBF1 , and IL6R as Direct Gene Targets of Epstein-Barr Virus (EBV) Nuclear Antigen 1 Critical for EBV-Infected B-Lymphocyte Survival

Tempera

Leo

Kossenkov

et al. 2016

J Virol

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Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is the EBV-encoded nuclear antigen and sequence-specific DNA binding protein required for viral origin binding and episome maintenance during latency. EBNA1 can also bind to numerous sites in the cellular genome and can provide a host cell survival function, but it is not yet known how EBNA1 sequence-specific binding is responsible for host cell survival. Here, we integrate EBNA1 chromatin immunoprecipitation sequencing (ChIP-Seq) with transcriptome sequencing (RNA-Seq) after EBNA1 depletion to identify cellular genes directly regulated by EBNA1 that are also essential for B-cell survival. We first compared EBNA1 ChIP-Seq patterns in four different EBV-positive cell types, including Burkitt lymphoma (BL) cells, nasopharyngeal carcinoma (NPC) cells, and lymphoblastoid cell lines (LCLs). EBNA1 binds to ϳ1,000 sites that are mostly invariant among cell types and share a consensus recognition motif. We found that a large subset of EBNA1 binding sites are located proximal to transcription start sites and correlate genome-wide with transcription activity. EBNA1 bound to genes of high significance for B-cell growth and function, including MEF2B, IL6R, and EBF1. EBNA1 depletion from latently infected LCLs results in the loss of cell proliferation and the loss of gene expression for some EBNA1-bound genes, including MEF2B, EBF1, and IL6R. Depletion of MEF2B, EBF1, or IL6R partially phenocopies EBNA1 depletion by decreasing the cell growth and viability of cells latently infected with EBV. These findings suggest that EBNA1 binds to a large cohort of cellular genes important for cell viability and implicates EBNA1 as a critical regulator of transcription of host cell genes important for enhanced survival of latently infected cells. IMPORTANCE Epstein-Barr virus (EBV) latent infection is responsible for a variety of lymphoid and epithelial cell malignancies. EBNA1 is the EBV-encoded nuclear antigen that is consistently expressed in all EBV-associated cancers. EBNA1 is known to provide a host cell survival function, but the mechanism is not known. EBNA1 is a sequence-specific binding protein important for viral genome maintenance during latency. Here, by integrating ChIP-Seq and RNA-Seq, we demonstrate that EBNA1 binds directly to the promoter regulatory regions and upregulates the transcription of host genes that are important for the survival of EBV-infected cells. Identification of EBNA1 target genes provides potential new targets for therapeutic intervention in EBV-associated disease.

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Section: Discussionmentioning

confidence: 99%

Identification of MEF2B , EBF1 , and IL6R as Direct Gene Targets of Epstein-Barr Virus (EBV) Nuclear Antigen 1 Critical for EBV-Infected B-Lymphocyte Survival

Tempera

Leo

Kossenkov

et al. 2016

J Virol

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“…These differences in ER stress effects on low-and high-copynumber LCLs may be related to epigenetic differences in LCLs derived from different patient sources. 21 Our results indicate that ER stress is an important in vitro trigger for lytic replication, and provide a chemical model for studying the cellular pathways involved. Our approach is validated by the fact that many of the same genes induced by lytic replication secondary to BCR cross-linking (eg, NR4A2 and EGR-1) are also up-regulated by ER-stress-induced lytic replication in our studies.…”

Section: Discussionmentioning

confidence: 66%

Endoplasmic reticulum stress causes EBV lytic replication

Taylor

Raghuwanshi

Rowe

et al. 2011

Blood

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“…We do not formally know if spontaneous lytic transcription results from intrinsic noise, such as gene-, network-, and cell-level variability that activates the BZLF1 promoter, or from environmental stimuli triggering signaling events sensed by EBV under physiological conditions. Levels of spontaneous reactivation in LCLs oscillate periodically [34]. Because cyclical processes suggest the presence of a changing stimulus, we suspect that spontaneous lytic transcription results from signaling events.…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus latency type and spontaneous reactivation predict lytic induction levels

Phan

Fernandez

Somberg

et al. 2016

Biochemical and Biophysical Research Communications

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The human Epstein-Barr virus (EBV) evades the immune system by entering a transcriptionally latent phase in B cells. EBV in tumor cells express distinct patterns of genes referred to as latency types. Viruses in tumor cells also display varying levels of lytic transcription resulting from spontaneous reactivation out of latency. We measured this dynamic range of lytic transcription with RNA deep sequencing and observed no correlation with EBV latency types among genetically different viruses, but type I cell lines reveal more spontaneous reactivation than isogenic type III cultures. We further determined that latency type and spontaneous reactivation levels predict the relative amount of induced reactivation generated by cytotoxic chemotherapy drugs. Our work has potential implications for personalizing medicine against EBV-transformed malignancies. Identifying latency type or measuring spontaneous reactivation may provide predictive power in treatment contexts where viral production should be either avoided or coerced.

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Cellular factors associated with latency and spontaneous Epstein–Barr virus reactivation in B-lymphoblastoid cell lines

Cited by 35 publications

References 84 publications

Identification of MEF2B , EBF1 , and IL6R as Direct Gene Targets of Epstein-Barr Virus (EBV) Nuclear Antigen 1 Critical for EBV-Infected B-Lymphocyte Survival

Identification of MEF2B , EBF1 , and IL6R as Direct Gene Targets of Epstein-Barr Virus (EBV) Nuclear Antigen 1 Critical for EBV-Infected B-Lymphocyte Survival

Endoplasmic reticulum stress causes EBV lytic replication

Epstein–Barr virus latency type and spontaneous reactivation predict lytic induction levels

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