The aryl hydrocarbon receptor (AhR) is a ligand inducible transcription factor (TF) with multiple endogenous and exogenous ligands. AhR regulates many cellular processes including differentiation, development, and xenobiotic metabolism. Among its exogenous ligands 2, 3, 7, 8 tetrachlorodibenzo-p-dioxin (TCDD) is its most potent inducer. Upon ligand binding, inactive cytosolic AhR undergoes a conformational change ultimately leading to its nuclear localization. Within the nucleus, AhR is thought to primarily dimerize with AhR nuclear translocator (ARNT) to form a functional TF which binds to DNA at dioxin response elements (DREs) and regulates transcription of AhR target genes. Most DREs in accessible chromatin are not bound by AhR, and DREs accessible in multiple cell lines or type can be bound in some and unbound in others. Still, since AhR possesses a strong core binding motif 5'-GCGTG-3', it is suited for a motif-centered analysis of its binding. To investigate determinants of AhR binding I developed interpretable machine learning models predicting the binding status of DREs in MCF-7, GM17212, HepG2 cells, and primary human hepatocytes. I conclude that AhR binding is driven by a complex interplay of cell-agnostic DRE flanking sequence and cell-specific local chromatin context.On the other hand, AhR can bind DNA in absence of ARNT. Both, RelA and KLF6 have been shown to physically interact with AhR and together drive the activation of several genes. For example, the activation of 1) c-myc in breast cancer and 2) PAI-1, p21cip1, and E-cadherin genes is driven by AhR interacting with RelA and KLF6, respectively. However, it is unknown if these interactions with AhR occur genome-wide or if they are localized to a small number of genes. I developed a computational method to investigate protein-protein interactions at AhR-bound sites. Results confirm ARNT as the main dimerization partner of AhR genome-wide in TCDD-exposed MCF-7 cells. By contrast, in untreated HepG2 cells, KLF6 and RelA but not ARNT were the main℗ dimerization partners of AhR. These findings indicate that the role of AhR is likely liganddependent and can potentially be explained through dimerization with different partners.
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