Photoaging is the premature aging of skin from exposure to natural and/or artificial sources of ultraviolet radiation, such as sunlight and indoor tanning beds. The changes in skin appearance due to photoaging are superimposed upon background changes from chronological aging. The dermal extracellular matrix (ECM) accumulates damage from solar ultraviolet radiation (UV) exposure that contributes to skin photoaging. The goal of this study was to evaluate the induction and reversibility of epigenetic alterations globally and at photoaging-related gene loci in human dermal fibroblasts (HDF) irradiated with solar simulated UVR (ssUVR). The analysis of gene expression using Affymetrix GeneChip arrays revealed significant responses to ssUVR ranging from the alteration of ∼300 genes with a single irradiation of 12 J/cm 2 ssUVR up to the alteration of ∼1,700 genes with chronic irradiation. The induction of many genes relevant to ECM maintenance and photoaging, such as matrix metalloproteinases (MMPs) and transforming growth factor beta (TGFβ) family proteins, were observed along with alterations to genes involved in epigenetic regulation, such as lysine acetyltransferases and lysine demethylases. Through using ChIP-PCR, it was demonstrated for the first time that exposure to ssUVR induced alterations of histone modifications in the promoters of MMP1, MMP2, MMP3, DPT, TGFβ1 and TGFβ2 that were consistent with ssUVR-induced gene expression alterations in HDF. However, these histone modification changes were not persistent or heritable. No significant alterations in DNA methylation that correlated with gene expression changes were found by pyrosequencing or MeDIP-PCR. Global alterations of histones were not observed following the irradiation of primary human dermal fibroblasts or reconstructed skin equivalents, but the persistent global decrease of histone H3 and H4 acetylation was found in immortalized human dermal fibroblasts BJ-5ta. Ascorbic acid and tocopherol were able to prevent acute ssUVR-induced gene expression changes, suggesting that oxidative stress from UVR may be responsible for the expression changes and possibly triggers the histone modification changes as well. An epigenetic mechanism linking UV exposure to photoaging would have a profound impact on our understanding of photoaging. The results of this study indicate that histone modifications and DNA methylation are altered in response to ssUVR. However, only some of these changes are consistent with mRNA level differences, while many others appear to be aberrant or not statistically significant and irreproducible. The observed histone modification changes in gene promoters that are consistent with mRNA level alterations appear to be temporary responses probably required to mediate the UVR stress response in fibroblasts.
|Commitee:||Burns, Fredrick, Cuddapah, Suresh, Klein, Catherine, Matsui, Mary, Tang, Moon-Shong|
|School:||New York University|
|Department:||Environmental Health Medicine|
|School Location:||United States -- New York|
|Source:||DAI-B 76/08(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Environmental Health, Aging|
|Keywords:||Dermal fibroblasts, Epigenetics, Histone, Methylation, Photoaging, Ultraviolet radiation|
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