NF-κB subunits direct kinetically distinct transcriptional cascades in antigen receptor-activated B cells

The nuclear factor kappa B (NF-& kappa;B) family of transcription factors orchestrates signal-induced gene expression in diverse cell types. Cellular responses to NF-& kappa;B activation are regulated at the level of cell and signal specificity, as well as differential use of family members (subunit specificity). Here we used time-dependent multi-omics to investigate the selective functions of Rel and RelA, two closely related NF-& kappa;B proteins, in primary B lymphocytes activated via the B cell receptor. Despite large numbers of shared binding sites genome wide, Rel and RelA directed kinetically distinct cascades of gene expression in activated B cells. Single-cell RNA sequencing revealed marked heterogeneity of Rel- and RelA-specific responses, and sequential binding of these factors was not a major mechanism of protracted transcription. Moreover, nuclear co-expression of Rel and RelA led to functional antagonism between the factors. By rigorously identifying the target genes of each NF-& kappa;B subunit, these studies provide insights into exclusive functions of Rel and RelA in immunity and cancer. Sen et al. provide in-depth temporal multi-omic analyses with single-cell RNA-sequencing (scRNA-seq) profiles of nuclear factor kappa B (NF-& kappa;B)-regulated gene expression in B cells upon B cell receptor (BCR) activation. Their findings reveal distinct kinetic patterns of gene expression mediated by RelA and Rel and functional antagonism between the closely related NF-& kappa;B subunits.