Epstein-Barr virus promotes survival through germinal center light zone chromatin architecture

BFL-1 is an understudied anti-apoptotic protein upregulated in cancer and Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines (LCLs). We have previously shown that BFL-1 is regulated through viral EBNA3A-mediated alterations in B-cell chromatin conformation (Price et al., 2017). Here, we extend those findings to define cis- and trans-acting factors that regulate BFL-1 in LCLs and reliance on BFL-1 for survival from extrinsic apoptosis. Beyond LCLs, BFL-1 is expressed in B cells maturing in the germinal center (GC). We therefore characterized the gene expression profiles and chromatin landscape of maturing human tonsillar B-cell subsets. While chromatin accessibility at the BFL-1 locus increases as naive B cells enter the GC reaction, BFL-1 expression increases during the transition from dark zone to light zone (LZ) correlating with association between enhancer regions and the transcriptional start site. The relationship between LCLs and LZ B cells suggests that EBV phenocopies GC biology to enhance their survival in establishing latent infection.