Single-cell characterization of transcriptomic heterogeneity in human tonsillar B-cell subsets

ABSTRACT: BFL-1 is an understudied anti-apoptotic protein that is upregulated in melanoma, certain forms of leukemias and lymphomas, and Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines (LCLs). We have previously shown that BFL-1 is upregulated in LCLs through a viral-mediated chromatin conformation. However, BFL-1 is also highly expressed in uninfected B cells undergoing maturation in the germinal center. We therefore sought to determine the non-viral mechanisms underlying BFL-1 upregulation in B cells. Here, we characterized the chromatin landscape of maturing B cell subsets found in human tonsillar lymphoid tissue. While chromatin accessibility at the BFL-1 locus increases as naïve B cells enter the germinal center reaction, we found that BFL-1 expression during the transition from dark zone to light zone correlates with a significant increase in three-dimensional chromatin association between upstream enhancer regions and the BFL-1 transcriptional start site (TSS). Interestingly, both LCLs and germinal center light zone B cells shared similar chromatin architectures at the BFL-1 TSS, suggesting a conserved mechanism underlying BFL-1 upregulation. Increased BFL-1 in LCLs also protects against FasL and TRAIL-activated extrinsic apoptosis. In addition to BFL-1 expression, LCLs and germinal center light zone B cells share similar patterns of gene expression, suggesting strong evidence that EBV infection phenocopies various aspects of the germinal center reaction. From this, we infer that EBV-infected B cells co-opts strategies from germinal center light zone B cells to upregulate BFL-1 and enhance their survival in establishing long-lived latent infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159674 | GEO | 2020/10/21

REPOSITORIES: GEO