The DNA loop release factor WAPL suppresses Epstein-Barr virus latent membrane protein expression to maintain the highly restricted latency I program

• Published in: PLoS pathogens 2024-09, Vol.20 (9), p.e1012525
• Main Authors: Murray-Nerger, Laura A, Maestri, Davide, Liu, Xiang, Li, Zhixuan, Auld, Nina R, Tempera, Italo, Teng, Mingxiang, Gewurz, Benjamin E
• Format: Article
• Language: English
• Subjects: B-Lymphocytes - metabolism; B-Lymphocytes - virology; Biology and Life Sciences; Burkitt Lymphoma - genetics; Burkitt Lymphoma - metabolism; Burkitt Lymphoma - virology; Cell Line, Tumor; Development and progression; DNA replication; Epstein-Barr virus diseases; Epstein-Barr Virus Infections - genetics; Epstein-Barr Virus Infections - metabolism; Epstein-Barr Virus Infections - virology; Gene expression; Gene Expression Regulation, Viral; Genetic aspects; Herpesvirus 4, Human - genetics; Humans; Medicine and health sciences; Membrane proteins; Physiological aspects; Short Reports; Viral Matrix Proteins - genetics; Viral Matrix Proteins - metabolism; Virus latency; Virus Latency - physiology; Virus research
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1012525

Epstein-Barr virus (EBV) uses latency programs to colonize the memory B-cell reservoir, and each program is associated with human malignancies. However, knowledge remains incomplete of epigenetic mechanisms that maintain the highly restricted latency I program, present in memory and Burkitt lymphoma cells, in which EBNA1 is the only EBV-encoded protein expressed. Given increasing appreciation that higher order chromatin architecture is an important determinant of viral and host gene expression, we investigated roles of Wings Apart-Like Protein Homolog (WAPL), a host factor that unloads cohesin to control DNA loop size and that was discovered as an EBNA2-associated protein. WAPL knockout (KO) in Burkitt cells de-repressed LMP1 and LMP2A expression, but not other EBV oncogenes, to yield a viral program reminiscent of EBV latency II, which is rarely observed in B-cells. WAPL KO also increased LMP1/2A levels in latency III lymphoblastoid cells. WAPL KO altered EBV genome architecture, triggering formation of DNA loops between the LMP promoter region and the EBV origins of lytic replication (oriLyt). Hi-C analysis further demonstrated that WAPL KO reprogrammed EBV genomic DNA looping. LMP1 and LMP2A de-repression correlated with decreased histone repressive marks at their promoters. We propose that EBV coopts WAPL to negatively regulate latent membrane protein expression to maintain Burkitt latency I.