Researchers Jos Smits and Jieqiong Qu investigated and uncovered this control mechanism that AHR regulates epidermal barrier function via transient activation of Transcription Factor AP-2 alpha (TFAP2A). The research groups led by Ellen van den Bogaard of the Department of Dermatology (Radboudumc) and Jo Huiqing Zhou of the Department of Molecular Developmental Biology (RIMLS-Science, Radboud university) published the results in a recent publication in Journal of Investigative Dermatology.
Through multidisciplinary teamwork, investigators combined advanced multi-omics technologies (RNA-sequencing, AHR-specific and H3K27ac-specific ChIP-sequencing) with epidermal keratinocyte cell models, epidermal organoids and biophysical measurements. They demonstrated that, upon AHR activation, the AHR transiently activates expression of a set of key transcription factors (e.g., TFAP2A) that initiate the terminal epidermal differentiation program. By CRISPR/Cas9 technologies, the role of the AHR-TFAP2A axis in controlling keratinocyte terminal differentiation and skin barrier function was confirmed. Overall, the study provides insights into the molecular mechanisms behind AHR-mediated barrier function and identifies potential targets and alternative routes for the treatment of common diseases showcasing aberrant differentiation and barrier dysfunction.