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, 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.

中文翻译：

---

芳基烃受体通过 TFAP2A 瞬时激活调节表皮分化

芳烃受体（AHR）是一种进化保守的环境传感器，被认为是上皮稳态和屏障器官功能不可或缺的调节剂。然而，AHR 激活时的分子信号级联和靶基因及其对细胞和组织功能的贡献尚未完全了解。使用人类皮肤角质形成细胞的多组学分析表明，配体激活后，AHR 结合开放染色质以诱导转录因子（例如 TFAP2A）的表达，作为对环境刺激的快速反应。终末分化程序，包括屏障基因和角蛋白的上调，由 TFAP2A 介导，作为 AHR 激活的次级反应。在人类表皮等效物中使用 CRISPR/Cas9 进一步证实了 AHR-TFAP2A 轴在控制角质形成细胞终末分化以形成适当屏障中的作用。总体而言，该研究为 AHR 介导的屏障功能背后的分子机制提供了更多见解，并确定了治疗皮肤屏障疾病的潜在靶标。