The Aryl Hydrocarbon Receptor Regulates Epidermal Differentiation through Transient Activation of TFAP2A.
Jos P H SmitsJieqiong QuFelicitas PardowNoa J M van den BrinkDiana Rodijk-OlthuisIvonne M J J van Vlijmen-WillemsSimon J van HeeringenPatrick L J M ZeeuwenJoost SchalkwijkHuiqing ZhouEllen H van den BogaardPublished in: The Journal of investigative dermatology (2024)
The aryl hydrocarbon receptor (AHR) is an evolutionary conserved environmental sensor identified as an indispensable regulator of epithelial homeostasis and barrier organ function. Molecular signaling cascade and target genes upon AHR activation and their contribution to cell and tissue function are however not fully understood. Multiomics analyses using human skin keratinocytes revealed that upon ligand activation, AHR binds open chromatin to induce expression of transcription factors, for example, TFAP2A, as a swift response to environmental stimuli. The terminal differentiation program, including upregulation of barrier genes, FLG and keratins, was mediated by TFAP2A as a secondary response to AHR activation. The role of AHR-TFAP2A axis in controlling keratinocyte terminal differentiation for proper barrier formation was further confirmed using CRISPR/Cas9 in human epidermal equivalents. Overall, the study provides additional insights into the molecular mechanism behind AHR-mediated barrier function and identifies potential targets for the treatment of skin barrier diseases.
Keyphrases
- genome wide
- transcription factor
- crispr cas
- poor prognosis
- wound healing
- endothelial cells
- single cell
- genome editing
- gene expression
- dna damage
- human health
- dna methylation
- genome wide identification
- oxidative stress
- risk assessment
- dna binding
- cell therapy
- signaling pathway
- single molecule
- climate change
- bioinformatics analysis
- induced pluripotent stem cells
- pluripotent stem cells