The transcription factors IRF4 and BLIMP1 (PRDM1) promote plasma cell (PC) differentiation by repressing B cell identity genes while inducing the unfolded protein response, ER/Golgi biogenesis, and immunoglobulin secretion. How IRF4 and BLIMP1 partition and coordinate their genomic activities during plasma cell differentiation remains unresolved. Using naive human B cells and a stepwise in vitro differentiation system, we performed CRISPR/Cas9 perturbations of IRF4 or PRDM1 in plasma cell precursors followed by single-cell RNA sequencing. Despite their mutually reinforced expression and shared recognition of related IRF-family motifs (ISREs and EICEs), loss of IRF4, but not of BLIMP1, yielded a stunted intermediate with incomplete silencing of B cell identity genes and defective induction of the secretory program. Multiome profiling, base-pair-resolution motif modeling, CUT&RUN, and DNA-binding assays identified non-conserved nucleotides within ISRE/EICE motifs that discriminate IRF4 from BLIMP1 binding. These findings reveal a motif-lexicon-dependent IRF4-BLIMP1 interplay, in which IRF4 first acts independently and then in concert with BLIMP1. This regulatory logic may also underlie programming of additional lymphocyte effector states.
Lau, L. C., Lal, S., Fan, J., Pease, N., Singh, H.
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