Interrogating in vivo Mechanisms of Kupffer Cell Transcriptional Regulation Using Natural Genetic Variation
Tissue macrophages are essential for the maintenance of organ homeostasis, but the cellular mechanisms specifying their phenotype are poorly understood. Here, we leverage natural genetic variation between inbred mouse strains as a tool to perturb Kupffer cell transcriptional regulation. We show that natural genetic variation disrupts Kupffer cell gene expression through cis-mediated disruption of transcription factor binding motifs and via trans-acting differences in the activity of gene regulatory machinery. We further divide trans-acting genetic variation into non-cell autonomous variation driven by changes in the Kupffer cell environment, and cell autonomous variation driven by changes in intracellular pathway activity. We show that careful evaluation of each mode of genetic variation can reveal signaling pathways specifying Kupffer cell identity in vivo. Collectively, this work demonstrates a novel approach for understanding how genetic diversity impacts tissue macrophage behavior.