Epstein-Barr Virus Expressed Long Non-Coding RNA (lncBARTs) Regulate EBV Latent Genome Replication

Abstract

Epstein-Barr virus (EBV) is a ubiquitous human virus that is also linked to various human cancers. In EBV-associated nasopharyngeal carcinoma and gastric carcinoma cells, EBV expresses only essential viral antigens but high levels of long non-coding RNAs known as BamHI-A rightward transcripts (lncBARTs). The exact roles lncBARTs in the EBV life cycle and the development of EBV-associated cancers are largely not understood. This study demonstrates that lncBARTs play a role in maintaining viral genome replication by affecting the tethering of EBV oriP region to chromosome. Mechanistically, lncBARTs interact functionally with a complex consisting of Bromodomain-containing protein 4 (BRD4), CCTC-binding factor (CTCF), and EBV nuclear antigen 1 (EBNA1), anchoring their binding at oriP to facilitate EBV episome replication. Additionally, the lncBARTs-BRD4/CTCF complex contributes to the regulation of MYC and BCL2 expression. These findings suggest that lncBARTs modulate EBV latency through interactions with oriP region, while lncBARTs-BRD4/CTCF complexes promote host epigenome reprogramming and drive tumorigenesis in EBV-associated epithelial tumors.