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Primary Keratinocyte Model of Actinic Keratosis Reveals UV-Induced DNA Damage Accumulation and Persistent Interferon Signaling

ABSTRACT: Actinic keratosis (AK) is a precancerous, UV-induced skin lesion that can progress to cutaneous squamous cell carcinoma (cSCC). While UV radiation is known to drive mutations and immunosuppression in the skin, keratinocyte-intrinsic responses to chronic, low-dose solar UV exposure have been insufficiently studied in AK. We established a patient-derived in vitro model using primary keratinocytes from AK lesions and age-matched, sun-exposed skin to investigate how repeated low-dose UV irradiation shapes keratinocyte stress responses. Integrating high-content morphological profiling, cyclobutane pyrimidine dimer (CPD) quantification and bulk RNA sequencing, we observed pronounced morphological remodeling and persistent DNA damage in AK keratinocytes despite activation of DNA repair and unfolded protein response pathways. Transcriptomic analyses revealed constitutive and UV-enhanced interferon signaling in AK cells, including upregulation of innate DNA sensing and ISGylation genes. Meta-analysis of five independent datasets confirmed interferon pathway activation as a conserved feature of AK, and IFN-α exposure further sensitized AK keratinocytes to UV-induced CPD formation. Our primary model thus uncovers sustained interferon signaling and attenuated DNA damage repair as key keratinocyte-intrinsic features of AK, suggesting that chronic interferon responses may modulate UV-induced damage and contribute to early photocarcinogenic processes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305980 | GEO | 2025/12/03

REPOSITORIES: GEO

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Project description:While several physiological skin parameters vary in a circadian manner, the identity of genes participating in chronobiology of skin remains unknown, leading us to define the circadian transcriptome of mouse skin at two different stages of the hair cycle, telogen and anagen. The circadian transcriptomes of telogen and anagen skin are largely distinct, with the former dominated by genes involved in cell proliferation and metabolism. The expression of many metabolic genes is antiphasic to cell cycle related genes, the former peaking during the day and the latter peaking at the night. Consistently, accumulation of reactive oxygen species, a byproduct of oxidative phosphorylation, and S-phase are antiphasic to each other in telogen skin. Furthermore, the circadian variation in S-phase is controlled by BMAL1 intrinsic to keratinocytes as keratinocyte-specific deletion of Bmal1 obliterates time of day dependent synchronicity of cell division in the epidermis leading to a constitutively elevated cell proliferation. Consistent with higher cellular susceptibility to UV-induced DNA damage during S phase, we found that mice are most sensitive to UVB-induced DNA damage in the epidermis at night. As maximum numbers of keratinocytes go through S phase in the late afternoon in the human epidermis, we speculate that in humans the circadian clock imposes regulation of epidermal cell proliferation such that skin is at a particularly vulnerable stage during times of maximum UV exposure, thus contributing to the high incidence of human skin cancers. Whole skin was collected at 4 hour intervals for 48 hours. ZT number indicates the number of hours elapsed from when lights are switched on. ZT0 = lights on (6am). ZT12=lights off (6pm). Total RNA was purified from the skin of each mouse and equal amount of RNA from the 3 replicates for each time point were pooled. Anagen samples were collected from skin of P30 male mice.

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