Fundamental molecular mechanisms of low dose radiation effects and adaptive responses

我的计划致力于低剂量辐射的生物效应、辐射适应及其与表观遗传学和基因组稳定性的关系的基础研究。它将解决一个根本性的重要问题：(I)小剂量的环境辐射对生物是否危险，(Ii)生物能否适应长期的辐射暴露，(Iii)辐射适应性反应的机制是什么？我提出了一种新的低剂量辐射效应和适应性反应的表观遗传学理论，据此，这些效应背后的机制受到表观遗传学的调控。表观遗传学改变包括基因表达的有丝分裂和减数分裂可遗传改变，这些改变不是由初级DNA序列的改变引起的，包括DNA甲基化、组蛋白修饰和小RNA介导的效应。在我的NSERC项目的任期内，我们分析了当生物体暴露在电离辐射(IR)中时，在更高水平的生物组织中观察到的表观遗传反应。我们证明了IR暴露会导致表观遗传学特征的深刻变化，并表明IR暴露会导致全球DNA甲基化、位点特异性DNA甲基化和组蛋白甲基化的显著变化。我们还表明IR诱导的表观遗传学变化与IR诱导的哺乳动物细胞基因组不稳定性和基因组重排有关。我们早期的研究已经提供了一些关于IR适应性反应的表观遗传学基础的初步证据。然而，了解低剂量辐射引起的表观遗传反应是一个关键但目前调查不足的研究领域，对于进一步从根本上理解生物如何处理和适应长期辐射暴露，以及开发适当的暴露生物标志物和对策至关重要。假设：我们假设DNA甲基化和羟基薄荷化以及调节的小RNA的变化与低剂量辐射诱导的基因组不稳定和适应性反应有关。我们预测，表观遗传变化可能会影响基因重排(DNA重组)的水平。这项研究的主要长期目标是剖析诱导IR诱导的基因组不稳定性和适应性反应的分子表观遗传学基础，并确定表观遗传学变化(即DNA甲基化、羟甲基化和小RNA)在LDR反应和适应性效应中的具体和基础作用。意义：了解暴露的细胞和生物体中发生的分子变化可能有助于制定措施，防止低剂量辐射暴露对生物体和种群的有害影响。我们将提供有关适应低剂量辐射的重要机制知识。

My program is devoted to fundamental studies on biological effects of low dose radiation, radio-adaptation and their relationship to epigenetics and genome stability. It will address a fundamentally important issues: (i) are small doses of environmental radiation dangerous for living organisms, (ii) can organisms adapt to protracted radiation exposure, (iii) what are the mechanisms of radiation adaptive responses? I propose a new epigenetic theory of low dose radiation effects and adaptive responses whereby the mechanisms that underlie these effects are epigenetically regulated. Epigenetic alterations comprise mitotically and meiotically heritable changes in gene expression that are not caused by changes in the primary DNA sequence and include DNA methylation, histone modifications and small RNA-mediated effects. During the tenure of my NSERC program we analyzed epigenetic responses observed in higher levels of biological organization when organisms are exposed to ionizing radiation (IR). We proved that IR exposures lead to profound alterations in the epigenetic profile, and have shown that IR exposure leads to significant alterations in global DNA methylation, locus-specific DNA methylation and histone methylation. We have also shown that IR-induced epigenetic changes are linked to IR-induced genome instability and genome rearrangements in mammalian cells. Our earlier studies have provided some of the first evidence as to epigenetic underpinnings of an adaptive response to IR. Nevertheless, understanding the low dose radiation-induced epigenetic responses is a critical but currently under-investigated area of research that is crucial for furthering our fundamental understanding of how organisms deal with protracted radiation exposure and adapt to it, and for the development of appropriate exposure biomarkers and countermeasures. Hypotheses: We hypothesize that changes in DNA methylation and hydroxymenthylation and regulatory small RNAs are associated with low dose radiation-induced genome instability and adaptive responses. We predict that epigenetic changes may influence levels of genetic rearrangements (DNA recombination). The main long-term goal of this research is to dissect the molecular epigenetic basis of induction of IR-induced genome instability and adaptive responses and identify the specific and fundamental roles of epigenetic changes (i.e. DNA methylation, hydroxymethylation and small RNAs) in LDR responses and adaptive effects. Significance: Understanding the molecular changes that occur in exposed cells and organisms may assist in the development of measures to prevent deleterious effects of low dose radiation exposure on organisms and populations. We will provide important mechanistic knowledge of the adaptation to low dose radiation.