Genome-Wide Transcriptional Profiling of Skin and Dorsal Root Ganglia after Ultraviolet-B-Induced Inflammation

Abstract

Ultraviolet-B (UVB)-induced inflammation produces a dose-dependent mechanical and thermal hyperalgesia in both humans and rats, most likely via inflammatory mediators acting at the site of injury. Previous work has shown that the gene expression of cytokines and chemokines is positively correlated between species and that these factors can contribute to UVB-induced pain. In order to investigate other potential pain mediators in this model we used RNA-seq to perform genome-wide transcriptional profiling in both human and rat skin at the peak of hyperalgesia. In addition we have also measured transcriptional changes in the L4 and L5 DRG of the rat model. Our data show that UVB irradiation produces a large number of transcriptional changes in the skin: 2186 and 3888 genes are significantly dysregulated in human and rat skin, respectively. The most highly up-regulated genes in human skin feature those encoding cytokines (IL6 and IL24), chemokines (CCL3, CCL20, CXCL1, CXCL2, CXCL3 and CXCL5), the prostanoid synthesising enzyme COX-2 and members of the keratin gene family. Overall there was a strong positive and significant correlation in gene expression between the human and rat (R = 0.8022). In contrast to the skin, only 39 genes were significantly dysregulated in the rat L4 and L5 DRGs, the majority of which had small fold change values. Amongst the most up-regulated genes in DRG were REG3B, CCL2 and VGF. Overall, our data shows that numerous genes were up-regulated in UVB irradiated skin at the peak of hyperalgesia in both human and rats. Many of the top up-regulated genes were cytokines and chemokines, highlighting again their potential as pain mediators. However many other genes were also up-regulated and might play a role in UVB-induced hyperalgesia. In addition, the strong gene expression correlation between species re-emphasises the value of the UVB model as translational tool to study inflammatory pain.

Ultraviolet Radiation on the Skin: A Painful Experience?

“…Another study examined molecular changes after UVB irradiation at the transcriptional level using RNA sequencing. By comparing skin samples of patients and rodents exposed to UVB, the authors presented a remarkable level of similarity across the different species, identifying changes on over 800 common genes . Most of the changes in expression were found in the skin, as previously reported .…”

“…Most of the changes in expression were found in the skin, as previously reported . Unsurprisingly, many of the genes upregulated were related to inflammation . The group also looked at molecular changes at the DRGs and identified 39 genes differentially regulated .…”

Adipochemokines induced by ultraviolet irradiation contribute to impaired fat metabolism in subcutaneous fat cells

“…Although some studies have demonstrated that UV irradiation induces distinct chemokines, such as CCL3, CCL20, CXCL1, CXCL2, CXCL3 and CXCL5 in human skin, these studies did not examine the expression or function of chemokines in isolated human SC fat tissues. CXCL5 is a proinflammatory chemokine that is linked to adipose tissue inflammation and insulin resistance, which antagonizes insulin signalling via the JAK‐STAT pathway .…”

Dynamics of chromatin accessibility and epigenetic state in response to UV damage

“…Recent evidence has suggested that chromatin plays a major role in the UV-induced cellular response including regulation of gene expression changes (Andrade-Lima et al, 2015;Dawes et al, 2014;Dinant et al, 2013;Duan and Smerdon, 2014;Hassan et al, 2014;Izhar et al, 2015;Li et al, 2014;Sesto et al, 2002;Zhang et al, 2014). However, a detailed genomewide analysis to investigate the relationship of chromatin and gene expression changes was still missing.…”

“…Consequences of DNA lesions, either as a result of UV irradiation or other genotoxic agents, to cell physiology are widely governed by changes in gene expression regulated on various levels (AndradeLima et al, 2015;Bowden et al, 2015;Dawes et al, 2014;Sesto et al, 2002). UVB has been shown to inhibit initiation of transcription by impeding the binding of RNA polymerase II to the promoters of many transcribed genes (Gyenis et al, 2014).…”