Fundamental molecular mechanisms of low dose radiation effects

点击翻译按钮获取中文摘要

Understanding the fundamental molecular mechanisms of low-dose ionizing radiation effects and in vivo adaptive responses has been one of the key research pillars of my laboratory. In 2003-2004 within the scope of my NSERC-funded program, we pioneered the studies in the area of radiation epigenetics. The current renewal of my NSERC program is based on my group’s key discoveries of the roles of epigenetic changes in radiation responses, and seeks to analyze in detail fundamental epigenetic changes that occur when organisms are exposed to low doses of radiation. We will focus on analysis of low dose radiation (LDR), whereby doses are comparable to those acquired due to occupational and environmental exposures (0.1 Gy and lower). Recently it has been shown that the biological effects of LDR are very complex, and that living organisms have a great capacity to adapt to radiation. The mechanisms of radiation-induced adaptive responses remain unexplained, and may be epigenetic in nature. Three major areas of epigenetics - DNA methylation and hydroxymethylation, histone modifications and small RNA-mediated silencing - are known to have profound effects on controlling gene expression. While the role of global DNA methylation in radiation responses was shown, the exact nature of this epigenetic phenomenon needs to be defined, and its roles in LDR effects needs to be established. Furthermore, the phenomenon of radiation effects has not been explored in the DNA hydroxymethylation domain. Additionally, the roles of small RNAs in LDR responses and radioadaptation need to be analyzed in more detail. The main long-term goal of the renewal of this NSERC program is to dissect the molecular epigenetic basis of induction of LDR-induced genome instability and adaptive responses and identify the specific and fundamental role of epigenetic changes (i.e., DNA methylation, hydroxymethylation and small RNAs) in these phenomena. The immediate objectives are: (i) to investigate the exact nature of global and locus-specific DNA methylation and DNA hydroxymethylation changes in LDR effects and adaptive responses; (ii) to dissect the roles of regulatory small RNAs in LDR effects and adaptive responses; (iii) to correlate the levels of epigenetic changes with the levels of cell proliferation, cell death, DNA damage, and genetic rearrangements, and (iv) to analyze age differences in adaptive responses. We will use cutting-edge deep sequencing approaches to characterize methylome, transcriptome and small RNAome to test our hypotheses and achieve our goals. This project will provide excellent training opportunities for several graduate and undergraduate students and postdocs. Besides uncovering the mechanisms and revealing the molecular epigenetic networks involved in LDR responses, the current project will address a fundamentally important issue: are low doses doses of environmental radiation dangerous for living organisms? Evaluating the hazards of environmental exposure is especially important nowadays, after the Fukushima radiation accident. Understanding the molecular changes that occur in exposed cells and organisms may assist in the development of measures to prevent deleterious LDR effects. The results obtained using the mouse model can potentially be extrapolated to other organisms. Thus, my program will provide important mechanistic knowledge of the response to LDR and help reduce the uncertainty of assessing risk at low doses.