191 Aryl hydrocarbon receptor controls epidermal differentiation and host defense response by regulation of AP1/AP2 transcription factor expression

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor which recently gained interest due to its regulatory role in many (patho)physiological processes and its potential as a drugable target. The AHR regulates epidermal proliferation and differentiation and is related to skin barrier function. How these AHR-dependent processes are molecularly regulated has yet to be elucidated. Using genome-wide transcriptomic and epigenomic analyses, we characterized gene regulatory events upon AHR activation in epidermal keratinocytes. We showed that early responsive genes induced by AHR activation were enriched for transcription factors, like TFAP2A (AP-2 family) and FOSL1 (AP-1 family), which are known to promote keratinocyte differentiation and host defense. Epidermal differentiation-related genes (e.g. filaggrin, keratins, transglutaminases) were identified as late responsive genes upon AHR activation. Knockdown of TFAP2A impeded differentiation gene expression, suggesting a newly identified AHR/TFAP2A axis in the control of epidermal differentiation and thus the formation of the physical skin barrier. Furthermore, the expression of a battery of antimicrobial host defence genes was found the be AHR-dependent indicating a novel role for the AHR in the chemical barrier function of the skin and host-microbe interactions (as evidenced by abstract #3232564 by Smits et al.). Our study pinpoints the AHR as a central regulator of skin barrier function and governance towards environmental and microbial challenges and underscores the importance of AHR signalling in skin homeostasis.