HSF4/COIL complex-dependent R-loop mediates ultraviolet-induced inflammatory skin injury

Intense ultraviolet (UV) exposure can cause phototoxic reactions, such as skin inflammation, resulting in injury. UV is a direct cause of DNA damage, but the mechanisms underlying transcriptional regulation within cells after DNA damage are unclear. The bioinformatics analysis of transcriptome sequencing data from UV-irradiated and non-UV-irradiated skin showed that transcription-related proteins, such as HSF4 and COIL, mediate cellular response to UV irradiation. HSF4 and COIL can form a complex under UV irradiation, and the preference for binding target genes changed because of the presence of a large number of R-loops in cells under UV irradiation and the ability of COIL to recognize R-loops. The regulation of target genes was altered by the HSF4-COIL complex, and the expression of inflammation and ageing-related genes, such as Atg7, Tfpi, and Lims1, was enhanced. A drug screen was performed for the recognition sites of COIL and R-loop. N6-(2-hydroxyethyl)-adenosine can competitively bind COIL and inhibit the binding of COIL to the R-loop. Thus, the activation of downstream inflammation-related genes and inflammatory skin injury was inhibited.

Automated summary

Intense UV exposure causes DNA damage and the cellular response to this damage is not well understood. Transcriptome analysis of UV-irradiated and non-irradiated skin revealed the involvement of transcription-related proteins HSF4 and COIL in mediating the cellular response to UV irradiation. Under UV irradiation, HSF4 and COIL form a complex and preferentially bind to target genes due to the presence of R-loops. This complex alters the regulation of target genes, leading to enhanced expression of inflammation and ageing-related genes, such as Atg7, Tfpi, and Lims1. A drug screening identified N6-(2-hydroxyethyl)-adenosine as a competitive inhibitor of COIL binding to R-loops, thereby inhibiting the activation of downstream inflammation-related genes and inflammatory skin injury.