Transcriptional profiles of IL-4 stimulated mouse peritoneal macrophages derived from different cellular lineages and of different genetics backgrounds

Interleukin-4 (IL-4) activates macrophages to adopt a distinct phenotype important for tissue repair and helminth infection, but the molecular basis of chromatin remodeling in response to IL-4 stimulation is not understood. We find that IL-4 activation of terminally differentiated macrophages in mice is accompanied by cell-type-specific chromatin remodeling in regions enriched with binding motifs of the pioneer transcription factor PU.1. Mutation studies based on natural genetic variation between C57BL/6 and BALB/c mouse strains demonstrate that accessibility of these IL-4 induced regions can be regulated through differences in DNA shape, without disruption of pioneer factor motifs. We propose a model whereby DNA shape features of stimulation-dependent genomic elements contribute to differences in the accessible chromatin landscape of alternatively activated macrophages on different genetic backgrounds. Overall design: We FACS-sorted IL-4 stimulated mouse peritoneal macrophages of F4/80hi CD206- (tissue resident) and F4/80int CD206+ (monocyte-derived) phenotypes for transcriptional profiling by CEL-Seq2 (Hashimshony et al, Genome Biology 2016).