Crucial role of TFAP2a in skin health unravelled

A comprehensive study revealed that an aryl hydrocarbon receptor (AhR)-TFAP2a axis plays a key role in different skin processes, such as the production of barrier and antimicrobial proteins. This finding may pave the way for TFAP2a-based therapies for skin conditions such as atopic dermatitis.

Atopic dermatitis is driven by Th2-cell-mediated inflammation and is characterised by acanthosis, spongiosis, skin barrier impairment, pruritus, and increased Staphylococcal colonisation in the skin microbiome. “Coal tar suppresses these changes, alleviates the symptoms, and is, therefore, a familiar product for the patients,” according to Dr Jos Smits (Radboud University Medical Center, the Netherlands) [1]. Coal tar is a mixture of thousands of polyaromatic hydrocarbons and exhibits anti-proliferative, anti-inflammatory, and antipruritic effects. “Polyaromatic hydrocarbons activate AhR,” explained Dr Smits. “These polyaromatic hydrocarbons are, in essence, carcinogenic due to prolonged activation of AhR. However, coal tar also contains AhR-inhibiting molecules. Therefore, it has not been linked to carcinogenic effects.” Coal tar also helps to modulate the skin microbiome by reducing Staphylococcus levels and increasing the growth of Cutibacterium acnes. Additionally, it reinforces the skin barrier by promoting the production of barrier proteins. However, coal tar is no longer a preferred treatment option due to its unpleasant odour, dark colour, potential photosensitisation, and limited availability.

The therapeutic mechanism of coal tar relies on the production of proteins. However, it is unclear which underlying mechanisms occur when coal tar activates AhRs. To explore this, Dr Smits and co-investigators exposed cultured skin cells to coal tar extract and 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), an AhR activator. “We used various omics techniques to assess how keratinocytes react to these substances,” said Dr Smits.

The results showed that, in the short term (within 2 hours), both coal tar and TCDD activated genes related to epithelium development and various metabolic pathways. About 10% of the activated genes were transcription factors. The long-term response (after 24 hours) was characterised by an increased expression of genes involved in peptide cross-linking, epidermal development, keratinocyte differentiation, and ATP biosynthesis. Notably, only 2% of the activated genes were transcription factors. “The transcription factors activated in the short term may occupy various parts of the cell DNA and may drive the later gene expression changes,” hypothesised Dr Smits.

The researchers observed that AhR signalling occurs through regions of open DNA, which are accessible for transcription factor binding. Dr Smits showed that RNA production was increased 2 hours after exposure to coal tar or TCDD and that AhRs bind to DNA encoding the transcription factor TFAP2. “This region of DNA was already open prior to AhR binding,” added Dr Smits.

Next, the team investigated whether TFAP2a is responsible for the expression of skin barrier-related genes and proteins. “We hypothesised that deleting TFAP2a through CRISPR/Cas9 would impair skin barrier production,” said Dr Smits. The analysis confirmed that blocking TFAP2a significantly reduced the expression of skin barrier-related genes and proteins (see Figure). The results persisted even when coal tar or TCDD were added after TFAP2a was inhibited.

Figure: The step-wise regulation of skin cell activity through aryl hydrocarbon receptors [1]



These findings highlight that TFAP2a plays an essential role in skin barrier formation and suggest that targeting this pathway could offer new therapeutic options for patients with atopic dermatitis.

1. Smits JPH, et al. The aryl hydrocarbon receptor regulates epidermal differentiation through transient activation of TFAP2A. Dermatologendagen 2025, 10–11 April, Apeldoorn, the Netherlands.

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Posted on 5 June 2025