Genome-wide screen of DNA methylation changes induced by low dose X-ray radiation in mice

• Published in: PloS one Vol. 9; no. 3; p. e90804
• Main Authors: Wang, Jingzi, Zhang, Youwei, Xu, Kai, Mao, Xiaobei, Xue, Lijun, Liu, Xiaobei, Yu, Hongjun, Chen, Longbang, Chu, Xiaoyuan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.03.2014; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Base Sequence; Biology; Chromatography; DNA; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation - genetics; DNA Methylation - radiation effects; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Radiation; Epigenetic inheritance; Gene Expression Regulation, Enzymologic - radiation effects; Gene Ontology; Genes; Genetic Association Studies; Genetic Testing; Genome - genetics; Genomics; High performance liquid chromatography; Ionizing radiation; Male; Medicine; Methylation; Methyltransferases; Mice, Inbred BALB C; Molecular Sequence Data; Occupational safety and health; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic - genetics; Radiation; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Sequence Analysis, DNA; Signal Transduction - genetics; Signal Transduction - radiation effects; Transcription Factor CHOP - metabolism; X-Rays
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0090804

Epigenetic mechanisms play a key role in non-targeted effects of radiation. The purpose of this study was to investigate global hypomethylation and promoter hypermethylation of particular genes induced by low dose radiation (LDR). Thirty male BALB/c mice were divided into 3 groups: control, acutely exposed (0.5 Gy X-rays), and chronic exposure for 10 days (0.05Gy/d×10d). High-performance liquid chromatography (HPLC) and MeDIP-quantitative polymerase chain reaction (qPCR) were used to study methylation profiles. DNMT1 and MBD2 expression was determined by qPCR and western blot assays. Methylation and expression of Rad23b and Ddit3 were determined by bisulfate sequencing primers (BSP) and qPCR, respectively. The results show that LDR induced genomic hypomethylation in blood 2 h postirraditaion, but was not retained at 1-month. DNMT1 and MBD2 were downregulated in a tissue-specific manner but did not persist. Specific hypermethylation was observed for 811 regions in the group receiving chronic exposure, which covered almost all key biological processes as indicated by GO and KEGG pathway analysis. Eight hypermethylated genes (Rad23b, Tdg, Ccnd1, Ddit3, Llgl1, Rasl11a, Tbx2, Scl6a15) were verified by MeDIP-qPCR. Among them, Rad23b and Ddit3 gene displayed tissue-specific methylation and downregulation, which persisted for 1-month postirradiation. Thus, LDR induced global hypomethylation and tissue-specific promoter hypermethylation of particular genes. Promoter hypermethylation, rather than global hypomethylation, was relatively stable. Dysregulation of methylation might be correlated with down-regulation of DNMT1 and MBD2, but much better understanding the molecular mechanisms involved in this process will require further study.