Naturally occurring polymorphisms reveal the cis-regulatory architecture priming marginal zone B cell differentiation 4467

Description The naïve splenic B cell compartment consists of follicular (FoB) and marginal zone (MZB) B cells. FoB maintain a quiescent state and can be found in circulation and secondary lymphoid organs. In contrast, MZB are exclusively located in the marginal zone and exist in a poised state, facilitating rapid responses to blood-borne pathogens in the absence of T cell help by generating a burst of plasma cells. MZB harbor a distinct genetic and epigenetic architecture; however, the transcription factor networks that underpin MZB activation, differentiation, and acquisition of effector functions are not fully understood. To address this, we crossed the wild-derived Spret/EiJ to C57BL/6 mice to generate an F1 hybrid mouse model with 40x106 genetic variants, allowing perturbations of the cis-regulatory genome. MZB and FoB were sorted from naive F1 mice and subjected to RNA and ATAC-sequencing. The genetic differences between the strains were used to map the data to a parent of origin allele and determine where the presence of a polymorphism resulted in an imbalance in accessibility and gene expression. These results identified genomic binding sites for retinoic acid and TGF-β induced signaling networks that are important drivers of the MZB transcriptional landscape. This approach provides insights into the functional B cell genome and reveals genetic features impacting TF binding, epigenetic architecture, and ultimately gene expression programs across differentiating B cells. Funding Sources This work was supported by NIH/NIAID R01AI148471, P01AI125180, and R01AI173252.