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Comparative RNA-Seq transcriptome analyses reveal dynamic time dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma

ABSTRACT: One of the health risks posed to astronauts during deep space flights is exposure to high charge, high-energy (HZE) ions (Z>13) which can lead to induction of hepatocellular carcinoma (HCC). We performed comparative RNA-Seq transcriptomic analysis to assess the carcinogenic effects of 600 MeV/n 56Fe (0.2 Gy), 1 GeV/n 16O (0.2 Gy), and 350 MeV/n 28Si (0.2 Gy) ions in a mouse model for radiation-induced hepatocellular carcinoma. C3H/HeNCrl mice were subjected to total body irradiation to simulate space HZE-irradiation environment and liver tissues were extracted at five different time points post-irradiation to investigate the time-dependent gradual carcinogenic response at the transcriptomic level. Our data demonstrated a clear difference in the effects of these HZE ions, particularly immunological, on the carcinogenic process of HCC, suggesting different molecular mechanisms of tumorigenesis. Also seen in this study was novel unmapped transcripts that were significantly affected by HZE. To investigate the biological functions of these transcripts, we used a machine learning technique known as self-organizing maps (SOMs) to characterize the transcriptome expression profiles of 60 samples (45 HZE-irradiated, 15 non-irradiated control) from liver tissues. A handful of localized modules in the maps emerged as groups of co-regulated and co-expressed transcripts. The functional context of these modules was discovered using overrepresentation analysis. We found that these spots typically contained enriched populations of transcripts related to specific immunological molecular processes. Taken together, these findings not only led to a better understanding of biological mechanisms underlying risks for HCC after HZE irradiation but also have important implications for discovery of potential countermeasures and identification of biomarkers of HZE-induced HCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE146254 | GEO | 2020/06/17

REPOSITORIES: GEO

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Project description:Human deep space and planetary travel is limited by uncertainties regarding the health risks associated with exposure to galactic cosmic radiation (GCR), and in particular the high linear energy transfer (LET), heavy ion component. Here we assessed the impact of two high-LET ions 56Fe and 28Si, and low-LET X rays on genome-wide methylation patterns in human bronchial epithelial cells. We found that all three radiation types induced rapid and stable changes in DNA methylation but at distinct subsets of CpG sites affecting different chromatin compartments. The 56Fe ions induced mostly hypermethylation, and primarily affected sites in open chromatin regions including enhancers, promoters and edges (“shores”) of CpG islands. The 28Si ion-exposure had mixed effects, inducing both hyper and hypomethylation and affecting sites in more repressed heterochromatic environments, whereas X rays induced mostly hypomethylation, primarily at sites in gene bodies and intergenic regions. Significantly, the methylation status of 56Fe ion irradiation sensitive sites, but not those affected by X ray or 28Si ions, could discriminate tumor from normal tissue for human lung adenocarcinomas and squamous cell carcinomas. Thus, high LET radiation exposure leaves a lasting imprint on the epigenome, and affects sites relevant to human lung cancer. The 56Fe ion signature may prove useful in monitoring the cumulative biological impact and associated cancer risks encountered by astronauts in deep space. Genome wide DNA methylation profiling of normal human bronchial epithelial cells irradiated with varying doses of 28Si-ion radiation ( 300 MeV/u at 0, 0.3, 1.0 Gy) , 56Fe-ion radiation (600 MeV/u at 0, 0.1, 0.3, 1.0 Gy) or X rays (320 kV at 0, 1.0 Gy). Triplicate control and irradiated samples were incubated and sampled at 4 timepoints between 2 and 62 days. The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across >485,000 CpGs from collected samples. Samples include: 56Fe ions, 4 doses x 4 time points x 3 replicates (4 removed in QC) = 44 samples; 28Si ions = 3 doses x 4 time points x 3 replicates = 36 samples; X ray, 2 doses x 4 time points x 3 replicates (2 removed in QC)= 22 samples.

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Comparative RNA-Seq transcriptome analyses reveal dynamic time dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma

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