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

Eileen Ruth S. Torres, Reed Hall, Gerd Bobe, Jaewoo Choi, Soren Impey, Carl Pelz, Jonathan R. Lindner, Jan F. Stevens, Jacob Raber

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Abstract

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.

Original languageEnglish (US)
Article number77
JournalFrontiers in Molecular Biosciences
Volume6
DOIs
StatePublished - Sep 10 2019

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Proton irradiation
Metabolomics
Biosynthesis
DNA Methylation
Transfer RNA
Heart Ventricles
Methylation
Protons
Hippocampus
Tissue
Amino Acyl-tRNA Synthetases
Amino acids
Amino Acids
Biomarkers
Down-Regulation
Brain
Metabolome
Radiation
Epigenomics

Keywords

  • hippocampus
  • integrated epigenetic metabolomics analysis
  • left ventricle
  • Parkinson's disease
  • proton irradiation
  • radiation biomarkers

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

Cite this

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title = "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",
abstract = "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.",
keywords = "hippocampus, integrated epigenetic metabolomics analysis, left ventricle, Parkinson's disease, proton irradiation, radiation biomarkers",
author = "Torres, {Eileen Ruth S.} and Reed Hall and Gerd Bobe and Jaewoo Choi and Soren Impey and Carl Pelz and Lindner, {Jonathan R.} and Stevens, {Jan F.} and Jacob Raber",
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T1 - 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

AU - Torres, Eileen Ruth S.

AU - Hall, Reed

AU - Bobe, Gerd

AU - Choi, Jaewoo

AU - Impey, Soren

AU - Pelz, Carl

AU - Lindner, Jonathan R.

AU - Stevens, Jan F.

AU - Raber, Jacob

PY - 2019/9/10

Y1 - 2019/9/10

N2 - 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.

AB - 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.

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