1. Perturbed DNA Methylation by Sustained Overexpression of Gadd45b Induces Chromatin Disorganization, DNA Strand Breaks and Dopaminergic Neuron Death in Mice
- Author
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Olivia Massiani-Beaudoin, Rajiv L. Joshi, Philippe Mailly, Julia Fuchs, Camille Ravel-Godreuil, Alain Prochiantz, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Collège de France (CdF (institution))
- Subjects
0303 health sciences ,050208 finance ,Heterochromatin ,DNA damage ,[SCCO.NEUR]Cognitive science/Neuroscience ,Neurodegeneration ,05 social sciences ,Biology ,medicine.disease ,Chromatin ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,DNA demethylation ,DNA methylation ,0502 economics and business ,medicine ,Heterochromatin maintenance ,Heterochromatin organization ,050207 economics ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Heterochromatin disorganization is a key hallmark of aging and DNA methylation state is currently the main molecular predictor of chronological age. The most frequent neurodegenerative diseases like Parkinson disease and Alzheimer’s disease are age-related but how the aging process and chromatin alterations are linked to neurodegeneration is unknown. Here, we investigated the consequences of viral overexpression of Gadd45b, a multifactorial protein involved in active DNA demethylation, in the midbrain of wild-type mice. Gadd45b overexpression induces global and stable changes in DNA methylation, particularly on gene bodies of genes related to neuronal functions. DNA methylation changes were accompanied by perturbed H3K9me3-marked heterochromatin and increased DNA damage. Prolonged Gadd45b expression resulted in dopaminergic neuron degeneration accompanied by altered expression of candidate genes related to heterochromatin maintenance, DNA methylation or Parkinson disease. Gadd45b overexpression rendered midbrain dopaminergic neurons more vulnerable to acute oxidative stress. Heterochromatin disorganization and DNA demethylation resulted in derepression of mostly young LINE-1 transposable elements, a potential source of DNA damage, prior to Gadd45b-induced neurodegeneration. Our data implicate that alterations in DNA methylation and heterochromatin organization, LINE-1 derepression and DNA damage can represent important contributors in the pathogenic mechanisms of dopaminergic neuron degeneration with potential implications for Parkinson disease.
- Published
- 2021