Naturally occurring polymorphisms reveal the cis-regulatory sites and transcription factors controlling follicular and marginal zone B cells

Abstract

Abstract The splenic B cell compartment consists of follicular (FoB) and marginal zone (MZB) B cells. In contrast to FoB, MZB exist in a poised state and rapidly respond to blood-borne pathogens in the absence of T cell help, predominately generating a rapid wave of short-lived plasma cells. These differences in responses are driven by differential genetic and epigenetic priming of each subset. MZB epigenetic programming are enriched for bHLH, POU, Rel and RUNT motifs, whereas FoB are enriched for IRF and KLF motifs. MZB also exhibit increased expression of genes associated with Notch signaling, Myc, and mTORC1 pathways. However, it is unclear how sequence specific transcription factors directly and indirectly regulate distinct states in MZB and FoB that underpin B cell activation, differentiation, and acquisition of effector functions. To address this, we generated an F1 hybrid model which utilizes naturally occurring polymorphism present in the wild-derived mouse line Spret/EiJ compared to the reference strain C57BL/6. The monoallelic polymorphisms present in this F1 generation allows us to use the allelic imbalance to dissect how alterations in genetic features impact TF binding, epigenetic architecture, and ultimately resulting gene expression programs. MZB and FoB were sorted from naive (Spret x B6) F1’s and subject to RNA and ATAC-seq. This study aims to define the cis-regulatory mechanisms responsible for the epigenetic and transcriptional differences of FoB and MZB cells.