Proton irradiation induces persistent and tissue-specific DNA methylation changes in the left ventricle and hippocampus

Impey, Soren; Pelz, Carl; Tafessu, Amanuel; Marzulla, Tessa; Turker, Mitchell S.; Raber, Jacob

doi:10.1186/s12864-016-2581-x

Cited by 37 publications

(56 citation statements)

References 57 publications

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“…Both 5mC and 5hmC in the brain are relatively persistent epigenetic marks [54, 55], but our recent work showed specific responses to radiation exposure for both DNA modifications [41]. That observation suggests an important role for DNA methylation (5mC and/or 5hmC) in brain function.…”

Section: Discussionmentioning

confidence: 92%

“…6a, neuronal categories indicated in green). Blue highlighted categories likely represent a generalized, as opposed to tissue specific, response to radiation exposure [41]. At the 0.1 Gy (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Comparing 0.1 and 0.2 Gy, overlap is observed in neuronal categories between regions with upregulated 5hmC (green). Blue highlighted categories are non-neuronal categories enriched across conditions that likely represent a generalized response to radiation exposure [41]. In general, the FDR-adjusted significance of shared neuronal and non-neuronal pathways was several orders of magnitude lower at the 20-week than the 2-week time point (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Some of the alterations in DNA methylation at the 2- and 20-week time point were not specific for 56 Fe ion irradiation and also seen at the 20-week time point following proton irradiation in another study [41]. For example, the non-neuronal category of cell adhesion was seen as a significant pathway for 0.1 Gy 5hmC up and 5hmC down at the 2- and 20-week time points and for 5mC down at the 2-week time point.…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported that a single exposure to proton irradiation caused long-term tissue specific changes in DNA methylation patterns that were present 22 weeks following exposure and that mapped to tissue specific pathways (hippocampus versus left ventricle) [41]. That study demonstrated that the brain epigenome is responsive to ionizing radiation.…”

Section: Introductionmentioning

confidence: 99%

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Short- and long-term effects of 56Fe irradiation on cognition and hippocampal DNA methylation and gene expression

et al. 2016

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BackgroundAstronauts are exposed to 56Fe ions that may pose a significant health hazard during and following prolonged missions in deep space. We showed previously that object recognition requiring the hippocampus, a structure critical for cognitive function, is affected in 2-month-old mice irradiated with 56Fe ions. Here we examined object recognition in 6-month-old mice irradiated with 56Fe ions, a biological age more relevant to the typical ages of astronauts. Moreover, because the mechanisms mediating the detrimental effects of 56Fe ions on hippocampal function are unclear, we examined changes in hippocampal networks involved in synaptic plasticity and memory, gene expression, and epigenetic changes in cytosine methylation (5mC) and hydroxymethylation (5hmC) that could accompany changes in gene expression. We assessed the effects of whole body 56Fe ion irradiation at early (2 weeks) and late (20 weeks) time points on hippocampus-dependent memory and hippocampal network stability, and whether these effects are associated with epigenetic changes in hippocampal DNA methylation (both 5mC and 5hmC) and gene expression.ResultsAt the two-week time point, object recognition and network stability were impaired following irradiation at the 0.1 and 0.4 Gy dose, but not following irradiation at the 0.2 Gy dose. No impairments in object recognition or network stability were seen at the 20-week time point at any irradiation dose used. Consistent with this pattern, the significance of pathways for gene categories for 5hmC was lower, though not eliminated, at the 20-week time point compared to the 2-week time point. Similarly, significant changes were observed for 5mC gene pathways at the 2-week time point, but no significant gene categories were observed at the 20-week time point. Only the 5hmC changes tracked with gene expression changes.ConclusionsDose- and time-dependent epigenomic remodeling in the hippocampus following 56Fe ion exposure correlates with behavioral changes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3110-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Short- and long-term effects of 56Fe irradiation on cognition and hippocampal DNA methylation and gene expression

et al. 2016

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The epigenetic component of the brain response to electromagnetic stimulation in Parkinson's Disease patients: A literature overview

Consales

Merla

Marino

et al. 2017

Bioelectromagnetics

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Modulations of epigenetic machinery, namely DNA methylation pattern, histone modification, and non-coding RNAs expression, have been recently included among the key determinants contributing to Parkinson's Disease (PD) aetiopathogenesis and response to therapy. Along this line of reasoning, a set of experimental findings are highlighting the epigenetic-based response to electromagnetic (EM) therapies used to alleviate PD symptomatology, mainly Deep Brain Stimulation (DBS) and Transcranial Magnetic Stimulation (TMS). Notwithstanding the proven efficacy of EM therapies, the precise molecular mechanisms underlying the brain response to these types of stimulations are still far from being elucidated. In this review we provide an overview of the epigenetic changes triggered by DBS and TMS in both PD patients and neurons from different experimental animal models. Furthermore, we also propose a critical overview of the exposure modalities currently applied, in order to evaluate the technical robustness and dosimetric control of the stimulation, which are key issues to be carefully assessed when new molecular findings emerge from experimental studies.

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Fifty-Hertz Magnetic Field Affects the Epigenetic Modulation of the miR-34b/c in Neuronal Cells

et al. 2017

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The exposure to extremely low-frequency magnetic fields (ELF-MFs) has been associated to increased risk of neurodegenerative diseases, although the underlying molecular mechanisms are still undefined. Since epigenetic modulation has been recently encountered among the key events leading to neuronal degeneration, we here aimed at assessing if the control of gene expression mediated by miRNAs, namely miRs-34, has any roles in driving neuronal cell response to 50-Hz (1 mT) magnetic field in vitro. We demonstrate that ELF-MFs drive an early reduction of the expression level of miR-34b and miR-34c in SH-SY5Y human neuroblastoma cells, as well as in mouse primary cortical neurons, by affecting the transcription of the common pri-miR-34. This modulation is not p53 dependent, but attributable to the hyper-methylation of the CpG island mapping within the miR-34b/c promoter. Incubation with N-acetyl-l-cysteine or glutathione ethyl-ester fails to restore miR-34b/c expression, suggesting that miRs-34 are not responsive to ELF-MF-induced oxidative stress. By contrast, we show that miRs-34 control reactive oxygen species production and affect mitochondrial oxidative stress triggered by ELF-MFs, likely by modulating mitochondria-related miR-34 targets identified by in silico analysis. We finally demonstrate that ELF-MFs alter the expression of the α-synuclein, which is specifically stimulated upon ELF-MFs exposure via both direct miR-34 targeting and oxidative stress. Altogether, our data highlight the potential of the ELF-MFs to tune redox homeostasis and epigenetic control of gene expression in vitro and shed light on the possible mechanism(s) producing detrimental effects and predisposing neurons to degeneration.

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Proton irradiation induces persistent and tissue-specific DNA methylation changes in the left ventricle and hippocampus

Cited by 37 publications

References 57 publications

Short- and long-term effects of 56Fe irradiation on cognition and hippocampal DNA methylation and gene expression

Short- and long-term effects of 56Fe irradiation on cognition and hippocampal DNA methylation and gene expression

The epigenetic component of the brain response to electromagnetic stimulation in Parkinson's Disease patients: A literature overview

Fifty-Hertz Magnetic Field Affects the Epigenetic Modulation of the miR-34b/c in Neuronal Cells

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