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

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Abstract

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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Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

B field:

Magnetic field

BSO:

Buthionine-s,r-sulfoximine

BTG4:

B cell translocation gene 4

5-mC:

5-Methyl cytosine

DAergic:

Dopaminergic

DAC:

5-Aza-2′-deoxycytidine

DHE:

Dihydroethidium

E field:

Electric field

ELF-MF:

Extremely low-frequency magnetic field

GSH:

Reduced glutathione

GSHest:

Reduced glutathione ethyl ester

H2-DCFDA:

2′,7′-Dichlorofluorescin diacetate

MicroRNAs/MiRs:

MicroRNAs

MF:

Magnetic field

MFI:

Mean fluorescence intensity

MPP+ :

1-Methyl-4-phenylpyridinium

NAC:

N-Acetyl-l-cysteine

PCNs:

Primary cortical neurons

PD:

Parkinson’s disease

PI:

Propidium iodide

PMA:

Phorbol 12-myristate 13-acetate

RA:

Retinoic acid

RMS:

Root-mean-square

ROS:

Reactive oxygen species

SNCA:

α-Synuclein

sncRNAs:

Small non-coding RNAs

3’UTR:

3′-Untranslated region

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Funding

G.F. was supported by grants from the Danish Cancer Society (R72-A4647; R146-A9414); the Italian Association for Cancer Research, (AIRC-MFAG 2011 n.1145) and is part of the Center of Excellence in Autophagy, Recycling and Disease (CARD), funded by the Danish National Research Foundation.

We are very grateful to Francesca Pacchierotti for her helpful criticisms and scientific support.

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Consales, C., Cirotti, C., Filomeni, G. et al. Fifty-Hertz Magnetic Field Affects the Epigenetic Modulation of the miR-34b/c in Neuronal Cells. Mol Neurobiol 55, 5698–5714 (2018). https://doi.org/10.1007/s12035-017-0791-0

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