Sequential and coordinated control of human plasma cell differentiation by IRF4 and BLIMP1 associated with a discriminating ISRE/EICE motif lexicon
- 1University of Pittsburgh
Abstract
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 define an ISRE/EICE motif lexicon that predicts differential IRF4 and BLIMP1 occupancy and are consistent with a temporally ordered model, in which IRF4 first acts independently and then in concert with BLIMP1 to promote PC differentiation.
Related
- Compensation Effect Amplification Control (CEAC): A movement-based approach for coordinated position and velocity control of the elbow of upper-limb prostheses
- Coordinated control of both microtubule ends regulates mitotic spindle length
- Sequential syntax of EEG microstates captures the temporal dynamics of inhibitory control
- Aging Is Associated with Reduced Topographic Differentiation Between Speaking and Silent Reading
- HOXA3 Knockdown Impairs hESC-Derived Thymic Epithelial-like Cell Differentiation and CXCL12-Associated Early T-Lineage Support
BibTeX
@misc{lau2026sequential,
title = {{Sequential and coordinated control of human plasma cell differentiation by IRF4 and BLIMP1 associated with a discriminating ISRE/EICE motif lexicon}},
author = {L. C. Lau and S. Lal and J. Fan and N. Pease and H. Singh},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.15.732353},
url = {https://www.biorxiv.org/content/10.64898/2026.06.15.732353v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Sequential and coordinated control of human plasma cell differentiation by IRF4 and BLIMP1 associated with a discriminating ISRE/EICE motif lexicon
AU - L. C. Lau
AU - S. Lal
AU - J. Fan
AU - N. Pease
AU - H. Singh
PY - 2026
DA - 2026/06/15
PB - bioRxiv
DO - 10.64898/2026.06.15.732353
UR - https://www.biorxiv.org/content/10.64898/2026.06.15.732353v2
AB - 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 define an ISRE/EICE motif lexicon that predicts differential IRF4 and BLIMP1 occupancy and are consistent with a temporally ordered model, in which IRF4 first acts independently and then in concert with BLIMP1 to promote PC differentiation.
ER -