Abstract
BackgroundHigh dose ionizing radiation (IR) induces potent toxic cell effects mediated by either direct DNA damage or the production of reactive oxygen species (ROS). IR-induced modulations in multiple biological processes have been proposed to be partly regulated by radiosensitive microRNA (miRNA). In order to gain new insights into the role of miRNAs in the regulation of biological processes after IR, we have investigated changes in mRNA and miRNA expression after high dose IR.ResultsIR induced changes in the mRNA and miRNA profiles of human peripheral blood mononuclear cells (PBMCs). When comparing non-irradiated and irradiated samples, we detected a time-dependent increase in differentially expressed mRNAs and miRNAs, with the highest differences detectable 20 hours after exposure. Gene ontology analysis revealed that very early events (up to 4 hours) after irradiation were specifically associated with p53 signaling and apoptotic pathways, whereas a large number of diverse cellular processes were deregulated after 20 hours. Transcription factor analysis of all up-regulated genes confirmed the importance of p53 in the early post-irradiation phase. When analyzing miRNA expression, we found 177 miRNAs that were significantly regulated in the late post-irradiation phase. Integrating miRNA and target gene expression data, we found a significant negative correlation between miRNA-mRNA and identified hepatic leukemia factor (HLF) as a transcription factor down-regulated in the response to IR. These regulated miRNAs and the HLF target genes were involved in modulating radio-responsive pathways, such as apoptosis, the MAKP signaling pathway, endocytosis, and cytokine-cytokine interactions.ConclusionUsing a large dataset of mRNA and miRNA expression profiles, we describe the interplay of mRNAs and miRNAs in the regulation of gene expression in response to IR at a posttranscriptional level and their involvement in the modulation of radiation-induced biological pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-814) contains supplementary material, which is available to authorized users.
Highlights
High dose ionizing radiation (IR) induces potent toxic cell effects mediated by either direct DNA damage or the production of reactive oxygen species (ROS)
Radio-responsive miRNAs As miRNAs are involved in multiple cellular processes and exert regulatory functions, we investigated whether IR induces changes in the miRNA expression levels in irradiated Peripheral blood mononuclear cells (PBMC)
In the second part of this study we investigated the extent to which IR induces changes in Messenger RNA (mRNA) and miRNA expression, whether miRNAs are involved in IR-induced gene expression alterations, and whether these gene expression modifications are reflected in corresponding protein concentrations
Summary
High dose ionizing radiation (IR) induces potent toxic cell effects mediated by either direct DNA damage or the production of reactive oxygen species (ROS). A wide range of different methods have been used to identify cellular responses to IR, ranging from the detection of chromosomal changes and cell viability assays to transcriptional profiling using gene expression array techniques [3,4,5,6,7,8,9]. The latter has acquired growing attention in the scientific community because it enables researchers to gain an excellent overview of molecular mechanisms that are altered in response to IR. The complex mechanisms underlying the altered biological processes after high dose radiation have still not been elucidated completely
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