Mapping chemical and genetic regulators of aryl hydrocarbon receptor signaling

Abstract

The human aryl hydrocarbon receptor (AHR) integrates chemical signals derived from the environment, gut microbes, and endogenous sources to regulate processes ranging from intestinal barrier integrity to xenobiotic detoxification. Despite strong evidence that dysregulation of AHR signaling is a causal factor in metabolic and auto-immune disorders, we currently lack a comprehensive understanding of the factors that regulate AHR activity in human cells. Here, we use genome-scale CRISPR screening to systematically identify regulators of AHR signaling in hepatocytes. The resulting datasets recapitulate the core AHR signaling pathway and identify a large network of regulators. Many of these factors have roles beyond AHR signaling, reflecting that AHR signaling is deeply integrated into human cell biology. We further dissect this network to reveal novel modes of regulation of AHR expression, protein levels, and signaling. Through complementary analyses, we also examine how AHR activation differs across cell types, highlighting the highly context-specific nature of AHR signaling. Together, our findings show that the activation and regulation of AHR varies with both cell type and ligand and reveal potential nodes for targeted modulation of AHR signaling for therapeutic benefit. Overall, our results define the regulatory network that underpins AHR activation, with implications for understanding host-microbe interactions, integrative chemosensation, and the etiology of metabolic and inflammatory disorders.