Integration of chromatin accessibility and gene expression data with cisREAD reveals a switch from PU.1/SPIB-driven to AP-1-driven gene regulation during B cell activation

Abstract

Human B cell differentiation into antibody secreting plasma cells is a critical process in the adaptive immune response, whose regulation at the genetic level remains incompletely understood. To reveal the temporal sequence of transcription factor driven cellular changes we generated chromatin accessibility (ATAC-seq) and gene expression (RNA-seq) data from in vitro differentiation of human B cells into plasma cells using a published protocol for differentiation up to the plasma cell stage. Using a new computational method, cisREAD (cis-Regulatory Elements Across Differentiation), we defined a core set of cis-regulatory elements that are confidently linked to dynamic transcription factor binding and changes in gene expression across the mature B lineage. Here we describe how cisREAD identifies regulatory element communities, based on chromatin accessibility and transcription factor co-occupancy, and prioritizes those whose accessibility predicts differential gene expression through regularized regression models. Through downstream analyses of cisREAD-predicted regulation, we show how transcription factors reshape B cell epigenomes and transcriptomes in response to differentiation stimuli. Our results confirm roles for OCT2, IRF4 and PRDM1 in plasma cell differentiation, and reveal that a shift from PU.1/SPIB-driven to AP-1-driven gene regulation is a key determinant of B cell activation. GRAPHICAL ABSTRACT O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY Integration of epigenomic and transcriptomic datasets with the cisREAD method, followed by clustering and network analysis, reveals that gene regulation shifts from PU.1/SPIB to AP-1 upon B cell activation. C_FIG_DISPLAY