Data_Sheet_1_Integrated Metabolomics-DNA Methylation Analysis Reveals Significant Long-Term Tissue-Dependent Directional Alterations in Aminoacyl-tRNA Biosynthesis in the Left Ventricle of the Heart and Hippocampus Following Proton Irradiation.ZIP

In this study, an untargeted metabolomics approach was used to assess the effects of proton irradiation (1 Gy of 150 MeV) on the metabolome and DNA methylation pattern in the murine hippocampus and left ventricle of the heart 22 weeks following exposure using an integrated metabolomics-DNA methylation analysis. The integrated metabolomics-DNA methylation analysis in both tissues revealed significant alterations in aminoacyl-tRNA biosynthesis, but the direction of change was tissue-dependent. Individual and total amino acid synthesis were downregulated in the left ventricle of proton-irradiated mice but were upregulated in the hippocampus of proton-irradiated mice. Amino acid tRNA synthetase methylation was mostly downregulated in the hippocampus of proton-irradiated mice, whereas no consistent methylation pattern was observed for amino acid tRNA synthetases in the left ventricle of proton-irradiated mice. Thus, proton irradiation causes long-term changes in the left ventricle and hippocampus in part through methylation-based epigenetic modifications. Integrated analysis of metabolomics and DNA methylation is a powerful approach to obtain converging evidence of pathways significantly affected. This in turn might identify biomarkers of the radiation response, help identify therapeutic targets, and assess the efficacy of mitigators directed at those targets to minimize, or even prevent detrimental long-term effects of proton irradiation on the heart and the brain.

本研究采用非靶向代谢组学方法，对小鼠海马体和心脏左心室在暴露于质子辐照（150 MeV 1 Gy）后22周内的代谢组及DNA甲基化模式进行了评估。通过整合代谢组学-甲基化分析，在两种组织中均揭示了氨基酸酰-tRNA生物合成方面的显著改变，但变化的趋势依赖于组织类型。质子辐照小鼠的左心室中，个体氨基酸和总氨基酸合成被下调，而在质子辐照小鼠的海马体中则被上调。氨基酸tRNA合成酶的甲基化在质子辐照小鼠的海马体中主要下调，而在质子辐照小鼠的左心室中未观察到一致的甲基化模式。因此，质子辐照通过基于甲基化的表观遗传修饰部分引起左心室和海马体的长期变化。代谢组学和DNA甲基化的整合分析是一种强大的方法，可获取受显著影响的途径的汇聚证据。这进而可能识别出辐射反应的生物标志物，帮助确定治疗靶点，并评估针对这些靶点的缓解剂的功效，以最小化或甚至预防质子辐照对心脏和大脑的长期有害影响。