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Published on: November 8, 2011
The Epstein-Barr virus EBNA1 protein modulates the alternative splicing of cellular genes
Simon Boudreault1, Victoria E S Armero1, Michelle S Scott1
1Département de biochimie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, J1E 4K8, Canada.
Background:
Alternative splicing (AS) is an important mRNA maturation step that allows increased variability and diversity of proteins in eukaryotes. AS is dysregulated in numerous diseases, and its implication in the carcinogenic process is well known. However, progress in understanding how oncogenic viruses modulate splicing, and how this modulation is involved in viral oncogenicity has been limited. Epstein-Barr virus (EBV) is involved in various cancers, and its EBNA1 oncoprotein is the only viral protein expressed in all EBV malignancies.
Methods:
In the present study, the ability of EBNA1 to modulate the AS of cellular genes was assessed using a high-throughput RT-PCR approach to examine AS in 1238 cancer-associated genes. RNA immunoprecipitation coupled to RNA sequencing (RIP-Seq) assays were also performed to identify cellular mRNAs bound by EBNA1.
Results:
Upon EBNA1 expression, we detected modifications to the AS profiles of 89 genes involved in cancer. Moreover, we show that EBNA1 modulates the expression levels of various splicing factors such as hnRNPA1, FOX-2, and SF1. Finally, RNA immunoprecipitation coupled to RIP-Seq assays demonstrate that EBNA1 immunoprecipitates specific cellular mRNAs, but not the ones that are spliced differently in EBNA1-expressing cells.
Conclusion:
The EBNA1 protein can modulate the AS profiles of numerous cellular genes. Interestingly, this modulation protein does not require the RNA binding activity of EBNA1. Overall, these findings underline the novel role of EBNA1 as a cellular splicing modulator.
Insights
Epstein-Barr virus EBNA1 protein alters cellular alternative splicing (AS) in 89 cancer-associated genes, independent of its RNA binding activity. This reveals a novel role for EBNA1 as a cellular splicing modulator in cancer development.
Area of Science:
- Molecular Biology
- Cancer Research
- Virology
Background:
- Alternative splicing (AS) generates protein diversity but its dysregulation is linked to cancer.
- Oncogenic viruses can modulate cellular splicing, yet mechanisms remain unclear.
- Epstein-Barr virus (EBV) is implicated in cancers, with its EBNA1 oncoprotein consistently expressed.
Purpose of the Study:
- To investigate how EBNA1 influences cellular alternative splicing.
- To identify cellular genes and splicing factors affected by EBNA1.
- To determine if EBNA1's RNA binding is necessary for splicing modulation.
Main Methods:
- High-throughput RT-PCR to analyze AS in 1238 cancer-associated genes.
- RNA immunoprecipitation coupled to RNA sequencing (RIP-Seq) to identify EBNA1-bound mRNAs.
- Assessment of splicing factor expression (hnRNPA1, FOX-2, SF1).
Main Results:
- EBNA1 expression altered AS profiles in 89 cancer-associated genes.
- EBNA1 modulated the expression of key splicing factors.
- RIP-Seq identified specific EBNA1-bound mRNAs, but not those with altered splicing.
Conclusions:
- EBNA1 protein modulates cellular gene alternative splicing profiles.
- This splicing modulation by EBNA1 does not require its RNA binding activity.
- EBNA1 functions as a novel cellular splicing modulator in the context of viral oncogenesis.
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