Radiation-induced skin fibrosis is a detrimental and chronic disorder that occurs after radiation exposure. DNA methylation has been characterized as an important regulatory mechanism of multiple pathological processes. In this study, we compared the genome-wide DNA methylation status in radiation-induced fibrotic skin and adjacent normal tissues of rats by methylated DNA immunoprecipitation sequencing. Radiation-induced fibrotic skin showed differentially methylated regions associated with 3,650 protein-coding genes, 72 microRNAs, 5,836 long noncoding RNAs and 3 piwi-interacting RNAs. By integrating the mRNA and methylation profiles, the zinc transporter SLC39A9/ZIP9 was investigated in greater detail. The protein level of ZIP9 was increased in irradiated skin tissues of humans, monkeys, and rats, especially in radiogenic fibrotic skin tissues. Radiation induced the demethylation of a CpG dinucleotide in exon 1 of ZIP9 that resulted in recruitment of the transcriptional factor Sp1 and increased ZIP9 expression. Overexpression of ZIP9 resulted in activation of the profibrotic transforming growth factor-b signaling pathway through protein kinase B in human fibroblasts. In addition, radiation-induced skin fibrosis was associated with increased zinc accumulation. The zinc chelator N,N,N',N'-tetrakis(2pyridylmethyl)-1,2-ethylenediamine abrogated ZIP9-induced activation of the transforming growth factor-b signaling pathway and attenuated radiation-induced skin fibrosis in a rat model. In summary, our findings illustrate epigenetic regulation of ZIP9 and its critical role in promoting radiation-induced skin fibrosis.
Radiation-induced lung injury is a major dose-limiting toxicity that occurs due to thoracic radiotherapy. Metabolomics is a powerful quantitative measurement of low-molecular-weight metabolites in response to environmental disturbances. However, the metabolomic profiles of radiation-induced lung injury have not been reported yet. In this study, male Sprague-Dawley rats were subjected to a single dose of 10 or 20 Gy irradiation to the right lung. One week after radiation, the obvious morphological alteration of lung tissues after radiation was observed by hematoxylin and eosin staining through a transmission electron microscope. We then analyzed the metabolites and related pathways of radiation-induced lung injury by gas chromatography–mass spectrometry, and a total of 453 metabolites were identified. Compared to the nonirradiated left lung, 19 metabolites (8 upregulated and 11 downregulated) showed a significant difference in 10 Gy irradiated lung tissues, including mucic acid, methyl-β-d-galactopyranoside, quinoline-4-carboxylic acid, and pyridoxine. There were 31 differential metabolites (16 upregulated and 15 downregulated) between 20 Gy irradiated and nonirradiated lung tissues, including taurine, piperine, 1,2,4-benzenetriol, and lactamide. The Kyoto Encyclopedia of Genes and Genomes–based pathway analysis enriched 32 metabolic pathways between the irradiated and nonirradiated lung tissues, including pyrimidine metabolism, ATP-binding cassette transporters, aminoacyl-tRNA biosynthesis, and β-alanine metabolism. Among the dysregulated metabolites, we found that taurine promoted clonogenic survival and reduced radiation-induced necrosis in human embryonic lung fibroblast (HELF) cells. This study provides evidence indicating that radiation induces metabolic alterations of the lung. These findings significantly advance our understanding of the pathophysiology of radiation-induced lung injury from the perspective of metabolism.
Radiation-induced gastric injury is a serious concern that may limit the duration and the delivered dose of radiation. However, the genome-wide molecular changes in stomach upon ionizing radiation have not been reported. In this study, mouse stomach was irradiated with 6 or 12 Gy X-ray irradiation and we found that radiation resulted in the atrophy of gastric mucosa and abnormal morphology of chief and parietal cells. Radiation-induced gastric injury was accompanied by an increase in the serum levels of pepsinogen A and pepsinogen C but not gastrin-17. The expression profiles of messenger RNA (mRNA) and long noncoding RNA (lncRNA) in normal and irradiated gastric tissues were measured by microarray analysis. Results revealed 17 upregulated and 10 downregulated mRNAs were consistent in 6 and 12 Gy irradiated gastric tissues, including D site-binding protein (Dbp) and fibrinogen-like protein 1 (Fgl1). Thirteen upregulated and 96 downregulated lncRNAs were commonly changed in 6 and 12 Gy irradiated gastric tissues. The dysregulated mRNAs were implicated in multiple pathways and showed coexpression with lncRNAs. To identify motifs for transcription factors and coactivators in the proximal promoter regions of the dysregulated RNAs, the bioinformatic tool Biopython was used. A variety of common motifs that are associated with transcription factors were identified, including ZNF263, LMX1B, and Dlx1. Our findings illustrate the molecular changes during radiation-induced gastric injury and the potential transcription factors driving this alteration.
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