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

Area of Science:

• Molecular Biology
• Dermatology
• Genetics

Background:

• Ultraviolet (UV) radiation causes DNA damage and phototoxic reactions, including skin inflammation.
• Mechanisms of transcriptional regulation following UV-induced DNA damage remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular mechanisms of cellular response to UV irradiation.
• To identify key proteins and pathways involved in UV-induced transcriptional dysregulation.
• To explore potential therapeutic targets for mitigating UV-induced skin damage.

Main Methods:

• Bioinformatic analysis of transcriptome sequencing data from UV-irradiated and non-irradiated skin.
• Identification and characterization of protein-protein interactions (HSF4-COIL complex).
• Investigation of R-loop recognition by COIL and its role in gene regulation.
• Drug screening to identify inhibitors of COIL-R-loop interaction.

Main Results:

• HSF4 and COIL were identified as key mediators of cellular response to UV irradiation.
• The HSF4-COIL complex formation under UV irradiation alters target gene binding preferences due to increased R-loops.
• COIL's ability to recognize R-loops influences the regulation of inflammation and aging-related genes (e.g., Atg7, Tfpi, Lims1).
• N6-(2-hydroxyethyl)-adenosine was identified as a compound that competitively binds COIL, inhibiting its interaction with R-loops.

Conclusions:

• The HSF4-COIL complex plays a critical role in UV-induced transcriptional changes and subsequent inflammatory responses.
• COIL's recognition of R-loops is a key mechanism in this process.
• Inhibiting the COIL-R-loop interaction with compounds like N6-(2-hydroxyethyl)-adenosine can prevent the activation of downstream inflammation-related genes and mitigate inflammatory skin injury.