Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective

Marshall, Lee; Killinger, Bryan A.; Ensink, Elizabeth; Li, Peipei; Li, Katie X.; Cui, Wei; Lubben, Noah; Weiland, Matthew; Wang, Xinhe; Gordevičius, Juozas; Coetzee, Gerhard A.; Ma, Jiyan; Jovinge, Stefan; Labrie, Viviane

doi:10.1038/s41593-020-0690-y

Cited by 64 publications

(73 citation statements)

References 127 publications

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“…Our previous study demonstrated the upregulation of TET2 in the cellular and animal model of PD, and further results indicated that TET2 knockdown attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairments in mice (14). Another recent study also confirmed that, patients with PD exhibit an epigenetic and transcriptional upregulation of TET2, while TET2 depletion in a neuronal cell model results in cytosine modification changes that are reciprocal to those observed in PD neurons (15). Therefore, the widespread epigenetic dysregulation of enhancers in the PD cellular and animal model may be partly mediated by an increased TET2 expression or its activity.…”

Section: Introductionmentioning

confidence: 71%

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SIRT1 Deacetylates TET2 and Promotes Its Ubiquitination Degradation to Achieve Neuroprotection Against Parkinson's Disease

Liu

et al. 2021

Front. Neurol.

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The epigenetic modifications, such as DNA methylation and histone acetylation, play a critical role in the pathogenesis of Parkinson's disease (PD). However, the relationship between DNA methylation and histone acetylation in PD is not fully understood. Previous studies have shown that patients with PD exhibit an epigenetic and transcriptional upregulation of Ten-Eleven Translocation 2 (TET2), a member of the DNA hydroxylases family. Silence information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, also plays a critical role in PD development and might be a potential target for PD therapy. Our previous data indicated that demethylation in the Cyclin-dependent kinase inhibitor 2A (CDKN2A) promoter by the TET2 directly activated its expression, then promoted the cell cycle arrest and cell death induced by 1-methyl-4-phenyl-pyridinium ion (MPP+). In this study, we found that the enzyme activity of SIRT1 is negatively correlated with the protein level of TET2. In addition, the deacetylation of TET2 induced by SIRT1 promotes TET2 degradation via the ubiquitin–proteasome pathway. Furthermore, the activation of endogenous SIRT1 by resveratrol (RV) leads to CDKN2A DNA hypermethylation due to the decreased TET2 protein levels, which relieves the inhibitory effect on CDK4 and upregulation of pRb, allowing cell proliferation and growth. Similar effects are observed for the inhibition of endogenous TET2 enzyme activity with TET2 inhibitor. Together, we discover a new mechanism by which the SIRT1-TET2-CDKN2A pathway is involved in the pathogenesis of PD, which may provide a potential target for PD treatment.

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Section: Introductionmentioning

confidence: 71%

“…In addition to regulating the cell cycle progression, which suppresses growth and induces cell cycle arrest and apoptosis of DA neurons in PD, TET2 inactivation in mice fully prevents nigral dopaminergic neuronal loss induced by previous inflammation. TET2 loss also attenuates transcriptional immune responses to an inflammatory trigger (15).…”

Section: Discussionmentioning

confidence: 99%

SIRT1 Deacetylates TET2 and Promotes Its Ubiquitination Degradation to Achieve Neuroprotection Against Parkinson's Disease

Liu

et al. 2021

Front. Neurol.

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“…A recent study has shown that Tet2 expression is increased in PD patients leading to altered 5mC patterns in enhancers of neuronal genes. Conversely, TET2 loss in mDA neurons was neuroprotective 51 . Tet2 did not show any changes in expression at either time point after AAV8- mGadd45b injection.…”

Section: Discussionmentioning

confidence: 96%

Perturbed DNA methylation by sustained overexpression of Gadd45b induces chromatin disorganization, DNA strand breaks and dopaminergic neuron death in mice

Ravel-Godreuil

Massiani‐Beaudoin

Mailly

et al. 2020

Preprint

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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.

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“…These findings place additional emphasis on investigation of ongoing functions of the TDG-BER pathway as elements of normal neuronal development rather that responses to accumulating DNA damage. Given these data, and recent studies linking Tet mutations to neurodegenerative disease (Cochran et al, 2020, p. 2; Marshall et al, 2020, p. 2), it is evident that further exploration of each of these three functions in the context of development, aging and degeneration will continue enhance our understanding of 5hmC and the brain.…”

Section: Discussionmentioning

confidence: 98%

5-hydroxymethylcytosine mediated active demethylation is required for neuronal differentiation and function

Stoyanova

Riad

2021

Preprint

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Although high levels of 5-hydroxymethylcytosine (5hmC) accumulate in neurons, it is not known whether 5hmC can serve as an intermediate in DNA demethylation in postmitotic neurons. We report high resolution mapping of DNA methylation and hydroxymethylation, chromatin accessibility, and histone marks in developing postmitotic Purkinje cells (PCs). Our data reveal new relationships between PC transcriptional and epigenetic programs, and identify a class of genes that lose both 5mC and 5hmC during terminal differentiation. Deletion of the 5hmC writers Tet1, Tet2, and Tet3 from postmitotic PCs prevents loss of 5mC and 5hmC in regulatory domains and gene bodies and hinders transcriptional and epigenetic developmental transitions, resulting in hyper-excitability and increased susceptibility to excitotoxic drugs. Our data demonstrate that Tet-mediated active DNA demethylation occurs in vivo, and that acquisition of the precise molecular and electrophysiological properties of adult PCs requires continued oxidation of 5mC to 5hmC during the final phases of differentiation.

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Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective

Cited by 64 publications

References 127 publications

SIRT1 Deacetylates TET2 and Promotes Its Ubiquitination Degradation to Achieve Neuroprotection Against Parkinson's Disease

SIRT1 Deacetylates TET2 and Promotes Its Ubiquitination Degradation to Achieve Neuroprotection Against Parkinson's Disease

Perturbed DNA methylation by sustained overexpression of Gadd45b induces chromatin disorganization, DNA strand breaks and dopaminergic neuron death in mice

5-hydroxymethylcytosine mediated active demethylation is required for neuronal differentiation and function

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