Molecular events in the epidermis upon aryl hydrocarbon receptor targeting: AHR-TFAP2A axis drives epidermal keratinocyte differentiation

The aryl hydrocarbon receptor (AHR) is an environmental sensor and ligand-activated transcription factor that is involved in epithelial homeostasis and barrier development of the skin. Through genome-wide transcriptomic and epigenomic analyses of human primary keratinocytes upon AHR activation using TCDD we identified early and late AHR responsive genes. The early responsive genes were enriched for canonical transcription factors known to promote keratinocyte differentiation, barrier development, and host defense, such as Transcription Factor AP-2α (TFAP2A). Genes related to epidermal differentiation and structure (e.g. filaggrin, keratins, and transglutaminases), and host defense (e.g. PI3 and S100 genes) were identified as late AHR responsive genes. DNA binding motif analysis and siRNA-based knockdown of TFAP2A expression in primary keratinocytes indicated that TFAP2A regulates late AHR responsive genes involved in epidermal differentiation. CRISPR-Cas9 mediated knockout of TFAP2A in keratinocytes resulted the severely impeded epidermal stratification, terminal differentiation, and additional functional barrier formation in 3D human epidermal equivalent cultures. The herein identified AHR-TFAP2A axis provides important insights into epidermal differentiation in response to environmental cues, which opens new avenues for the targeting of this axis to treat barrier dysfunction related diseases.