Fundamental molecular mechanisms of low dose radiation effects and adaptive responses

我的计划致力于低剂量辐射，辐射适应及其与表观遗传学和基因组稳定性的关系的生物学效应的基础研究。它将解决一个根本性的重要问题：（一）小剂量的环境辐射对生物体是否有危险，（二）生物体能否适应长期的辐射照射，（三）辐射适应性反应的机制是什么？我提出了一个新的低剂量辐射效应和适应性反应的表观遗传理论，这些影响的基础机制是表观遗传调节。表观遗传改变包括基因表达中的有丝分裂和减数分裂可遗传的变化，这些变化不是由一级DNA序列的变化引起的，并且包括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于电离辐射（IR）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暴露导致表观遗传谱的深刻改变，并且已经表明IR暴露导致全局DNA甲基化、基因座特异性DNA甲基化和组蛋白甲基化的显著改变。我们还表明，IR诱导的表观遗传变化与哺乳动物细胞中IR诱导的基因组不稳定性和基因组重排有关。我们早期的研究提供了一些关于对IR的适应性反应的表观遗传基础的第一批证据。然而，了解低剂量辐射诱导的表观遗传反应是一个关键但目前研究不足的研究领域，这对于进一步了解生物体如何处理长期辐射暴露并适应它至关重要，以及开发适当的暴露生物标志物和对策。假设：我们假设DNA甲基化和羟甲基化以及调节性小RNA的变化与低剂量辐射诱导的基因组不稳定性和适应性反应有关。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。本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基础，并确定表观遗传变化（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本作用。重要性：了解受照射细胞和生物体中发生的分子变化可能有助于制定措施，防止低剂量辐射照射对生物体和种群的有害影响。我们将提供重要的机制知识的适应低剂量辐射。

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.