Solar Simulated Ultraviolet Radiation Induces Global Histone Hypoacetylation in Human Keratinocytes

Abstract

Ultraviolet radiation (UVR) from sunlight is the primary effector of skin DNA damage. Chromatin remodeling and histone post-translational modification (PTM) are critical factors in repairing DNA damage and maintaining genomic integrity, however, the dynamic changes of histone marks in response to solar UVR are not well characterized. Here we report global changes in histone PTMs induced by solar simulated UVR (ssUVR). A decrease in lysine acetylation of histones H3 and H4, particularly at positions of H3 lysine 9, lysine 56, H4 lysine 5, and lysine 16, was found in human keratinocytes exposed to ssUVR. These acetylation changes were highly associated with ssUVR in a dose-dependent and time-specific manner. Interestingly, H4K16ac, a mark that is crucial for higher order chromatin structure, exhibited a persistent reduction by ssUVR that was transmitted through multiple cell divisions. In addition, the enzymatic activities of histone acetyltransferases were significantly reduced in irradiated cells, which may account for decreased global acetylation. Moreover, depletion of histone deacetylase SIRT1 in keratinocytes rescued ssUVR-induced H4K16 hypoacetylation. These results indicate that ssUVR affects both HDAC and HAT activities, leading to reduced histone acetylation.

Transcription factors and stress response gene alterations in human keratinocytes following Solar Simulated Ultra Violet Radiation

“…Our previous study demonstrated a massive reduction of histone lysine acetylation in human keratinocytes exposed to ssUVR 24 . As histone acetylation is normally associated with active gene expression, it is quite surprising that the numbers of up-regulated and down-related genes are equally represented in most comparison conducted in our study, with the exception of cells exposed to repetitive ssUVR at 3 J/cm 2 .…”

“…The range of doses used in the study is comparable to what a person would be exposed to when standing outside for 40 minutes (3 J/cm 2 ) to 2.5 hours (12 J/cm 2 ) at noon under a clear sky with a UV index of 6 or higher 24 . Our previous study found that HaCaT cells exposed to a single dose of 12 J/cm 2 exhibited a moderate increase of phosphorylated histone variant H2AX, a well-characterized marker of DNA damage, at 1 hour post irradiation, as well as limited cell death (less than 20%) at 24 hours after irradiation 24 . Irradiated cells were harvested 24 hours post irradiation and subjected to transcriptional profiling.…”

“…The UV source and simulated UV radiation are the same as previously described 24 . Solar simulated UV radiation was performed using a modified Hand Foot II phototherapy instrument (National Biological Corporation, Beachwood, OH) with 8 UVA lamps (HOUVALITE F24T12/BL/HO [PUVA], National Biological Corporation).…”

“…We previously investigated global changes of histone post-translational modifications in human keratinocytes exposed to solar simulated UVR (ssUVR composing 95% UVA and 5% UVB) 24 . The acetylation of several lysine residues located on histone H3 and H4 was reduced after either a single dose of radiation or 3–5 repetitive exposure of ssUVR.…”

Molecular Mechanisms and Biomarkers of Skin Photocarcinogenesis

“…Upon further analysis, UV-induced differential H3K27ac acetylation was functionally correlated with differential gene expression was observed [76]. The genome wide loss of H3K27ac may be attributable to the suppression of histone acetyltransferases activities, whereas the regional gain of H3K27ac may occur secondary to the binding of UV-responsive transcription factors, such as JUN/FOS or TP53, which subsequently recruit HATs to their target regions [76,77]. Though the epigenetic mechanisms underlying the effects of UVR in promoting skin cancer warrant more extensive studies, the use of histone biomarkers for clinical diagnosis and/or prognosis is an interesting approach that is also being investigated for use in other malignancies [78,79].…”