Epstein-Barr virus (EBV) is a DNA tumor virus isolated from African Burkitt’s lymphoma samples. It belongs to the γ-subfamily of the herpes virus and approximately causes 200,000 cases of different cancers annually. EBNA2 is one of the first genes expressed upon EBV infection and essential for EBV-transformed cells establishment, continuous proliferation, and survival. As an important EBV transcription factor, EBNA2 activates the expression of other EBV latent genes and cellular genes by tethered to viral and cellular gene regulatory elements through cellular transcription factors. Phase separation is a process in which a single liquid phase comprising mutually soluble components demixes into two or more phases. Phase separation is linked to spatiotemporal regulation of gene expression. Dr. Jian Ma’s group previously revealed that EBNA2 activates cellular genes transcription by phase separation (J Virology, 2020).

Alternative splicing of pre-mRNAs generates a wide variety of differentially spliced RNA transcripts, which greatly enriches the repertoire of the proteome and contributes to temporal and spatial diversification of biological function.

Recently, Ma’s group identified that EBV EBNA2 interacts with components of the splicing machinery.They discovered more than 2000 EBNA2-affected alternative splicing events by integrating SMRT sequencing (the third-generation sequencing technique) and RNA-sequencing, with a preference for exon skipping in genes involved with carcinogenic process such asHRAS. In addition, They evaluated the biological impact of EBAN2-affected alternative splicing events, and one novel candidatesMPPE1were selected whose alternative splicing correlated with EBNA2 expression. Particularly, EBNA2 regulatesMPPE1aberrant splicing by recruiting SRSF1 and SRSF7. Moreover, the abilities of EBNA2 in regulating gene splicing require EBNA2 phase separation. These foundings highlight a foundation for understanding the mechanism that EBNA2-mediated alternative splicing events as a potential key player in EBV-host interactions, which previously has not been appreciated.

This study has been reported in the journalClinical and Translational Medicine(PMID: 34459139). Ph.D. student Qiu Peng is the first author, and Dr. Jian Ma (Cancer Research Institute of School of Basic Medical Science, Central South University) is thecorresponding author.