Novel Gene Regulation Mechanisms of Aryl Hydrocarbon Receptor: A ChIP-seq and RNA-seq Study of Ahrdbd/dbd Mice Expressing an Aryl Hydrocarbon Receptor with Mutated DNA-binding Domain

Aryl hydrocarbon receptor (AHR) is a transcription factor known for mediating the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and regulating many physiological and pathological processes. In its canonical signalling pathway, ligand-activated AHR translocates into nucleus, associates with its heterodimerization partner, and binds the cognate aryl hydrocarbon response element (AHRE) to regulate transcription. Based on recent evidence, we hypothesize that AHR may mediate gene regulation through unrevealed mechanisms, namely indirect DNA binding via tethering to other transcription factors, or direct DNA binding to regions not containing any AHRE. To explore this, Ahrdbd/dbd mice whose AHR is incapable of binding AHRE were used. ChIP-seq showed Ahrdbd/dbd mice indeed had an increased number of AHR-bound regions across the genome upon activation by TCDD. However, RNA-seq found almost no alteration in gene expression. These results support the presence but refute the physiological significance of AHR tethering to other transcription factors or non-AHRE binding to DNA.M.Sc