Effects of High-Dose Ionizing Radiation in Human Gene Expression: A Meta-Analysis.

The use of high-dose Ionizing Radiation (IR) is currently one of the most common modalities in treatment of many types of cancer. The objective of this work was to investigate the effects of high-dose ionizing radiation on healthy human tissue, utilizing quantitative analysis of gene expression. To this end, publicly available transcriptomics datasets from human samples irradiated with a high dose of radiation and non-irradiated (control) ones were selected, and gene expression was determined using RNA-Seq data analysis. Raw data from these studies were subjected to quality control and trimming. Mapping of RNA-Seq reads was performed by the partial selective alignment method, and differential gene expression analysis was conducted. Subsequently, a meta-analysis was performed to select differentially expressed genes across datasets. Based on the differentially expressed genes discovered by meta-analysis, we constructed a protein-to-protein interaction network, and we identified biological pathways and processes related to high-dose IR effects. Our findings suggest that cell cycle arrest is activated, supported by our top down-regulated genes associated with cell cycle activation. DNA repair genes are down-regulated in their majority. However, several genes implicated in the nucleotide excision repair pathway are upregulated. Nevertheless, apoptotic mechanisms seem to be activated probably due to severe high-dose-induced complex DNA damage. The significant upregulation of CDKN1A, as a downstream gene of TP53, further validates programmed cell death. Finally, down-regulation of TIMELESS, signifies a correlation between IR response and circadian rhythm. Nonetheless, high-dose IR exposure effects regarding normal tissue (radiation toxicity) and its possible long-term outcomes should be studied to a greater extend.

Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits.

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.

A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression.

The use of high linear energy transfer (LET) ionizing radiation (IR) is progressively being incorporated in radiation therapy due to its precise dose localization and high relative biological effectiveness. At the same time, these benefits of particle radiation become a high risk for astronauts in the case of inevitable cosmic radiation exposure. Nonetheless, DNA Damage Response (DDR) activated via complex DNA damage in healthy tissue, occurring from such types of radiation, may be instrumental in the induction of various chronic and late effects. An approach to elucidating the possible underlying mechanisms is studying alterations in gene expression. To this end, we identified differentially expressed genes (DEGs) in high Z and high energy (HZE) particle-, γ-ray- and X-ray-exposed healthy human tissues, utilizing microarray data available in public repositories. Differential gene expression analysis (DGEA) was conducted using the R programming language. Consequently, four separate meta-analyses were conducted, after DEG lists were grouped depending on radiation type, radiation dose and time of collection post-irradiation. To highlight the biological background of each meta-analysis group, functional enrichment analysis and biological network construction were conducted. For HZE particle exposure at 8-24 h post-irradiation, the most interesting finding is the variety of DNA repair mechanisms that were downregulated, a fact that is probably correlated with complex DNA damage formation. Simultaneously, after X-ray exposure during the same hours after irradiation, DNA repair mechanisms continue to take place. Finally, in a further comparison of low- and high-LET radiation effects, the most prominent result is that autophagy mechanisms seem to persist and that adaptive immune induction seems to be present. Such bioinformatics approaches may aid in obtaining an overview of the cellular response to high-LET particles. Understanding these response mechanisms can consequently aid in the development of countermeasures for future space missions and ameliorate heavy ion treatments.