DNA Methylation in Neurodegenerative Diseases

Fedotova, E. Yu.; Illarioshkin, S. N.

doi:10.1134/s1022795419030062

Cited by 9 publications

(8 citation statements)

References 57 publications

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“…For example, DNA methylation plays a pivotal role in the long-term transcriptional silencing seen with genomic imprinting, X chromosome inactivation, and the silencing of repetitive elements (Bird, 2002;Weber and Schubeler, 2007). The depletion of enzymes that catalyze DNA methylation or DNA demethylation leads to a diversity of developmental disorders, including severe neurological defects (Edwards et al, 2017;Fedotova and Illarioshkin, 2019;Kumar et al, 2018;Ross and Bogdanovic, 2019;Wu and Zhang, 2017;Wu et al, 2018). Many studies support that DNA methylation is a central regulator of cell identity (Bogdanovic and Lister, 2017;Wu et al, 2018;Zeng and Chen, 2019).…”

Section: Roles For Dna Methylation In Animal Developmentmentioning

confidence: 99%

DNA methylation dynamics underlie metamorphic gene regulation programs in Xenopus tadpole brain

Kyono

Raj

Sifuentes

et al. 2020

Developmental Biology

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Methylation of cytosine residues in DNA influences chromatin structure and gene transcription, and its regulation is crucial for brain development. There is mounting evidence that DNA methylation can be modulated by hormone signaling. We analyzed genome-wide changes in DNA methylation and their relationship to gene regulation in the brain of Xenopus tadpoles during metamorphosis, a thyroid hormone-dependent developmental process. We studied the region of the tadpole brain containing neurosecretory neurons that control pituitary hormone secretion, a region that is highly responsive to thyroid hormone action. Using Methylated DNA Capture sequencing (MethylCap-seq) we discovered a diverse landscape of DNA methylation across the tadpole neural cell genome, and pairwise stage comparisons identified several thousand differentially methylated regions (DMRs). During the pre-to pro-metamorphic period, the number of DMRs was lowest (1,163), with demethylation predominating. From pre-metamorphosis to metamorphic climax DMRs nearly doubled (2,204), with methylation predominating. The largest changes in DNA methylation were seen from metamorphic climax to the completion of metamorphosis (2960 DMRs), with 80% of the DMRs representing demethylation. Using RNA sequencing, we found negative correlations between differentially expressed genes and DMRs localized to gene bodies and regions upstream of transcription start sites. DNA demethylation at metamorphosis revealed by MethylCap-seq was corroborated by increased immunoreactivity for the DNA demethylation intermediates 5-hydroxymethylcytosine and 5-carboxymethylcytosine, and the methylcytosine dioxygenase ten eleven translocation 3 that catalyzes DNA demethylation. Our findings show that the genome of tadpole neural cells undergoes significant changes in DNA methylation during metamorphosis, and these changes likely influence chromatin architecture, and gene regulation programs occurring during this developmental period.

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Section: Roles For Dna Methylation In Animal Developmentmentioning

confidence: 99%

DNA methylation dynamics underlie metamorphic gene regulation programs in Xenopus tadpole brain

Kyono

Raj

Sifuentes

et al. 2020

Developmental Biology

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“…Out of these DNMT1 is primarily involved in the maintenance of methylation signatures on DNA. In Alzheimer’s disease, there are evidences of decreased 5mC levels and DNA methyl transferase 1 (DNMT1) in the hippocampal and temporal brain region [ 68 , 69 ]. However, in another study, increased levels of DNA methylation and DNMTs have been found in frontal cortex, temporal cortex and cerebellum [ 70 – 72 ].…”

Section: Methylation As a Mode Of Epigenetic Regulation And Its Role In Alzheimer’s Diseasementioning

confidence: 99%

Methylation as a key regulator of Tau aggregation and neuronal health in Alzheimer’s disease

Balmik

Chinnathambi

2021

Cell Commun Signal

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Neurodegenerative diseases like Alzheimer’s, Parkinson’s and Huntington’s disease involves abnormal aggregation and accumulation of toxic proteins aggregates. Post-translational modifications (PTMs) of the causative proteins play an important role in the etiology of disease as they could either slow down or accelerate the disease progression. Alzheimer disease is associated with the aggregation and accumulation of two major protein aggregates—intracellular neurofibrillary tangles made up of microtubule-associated protein Tau and extracellular Amyloid-β plaques. Post-translational modifications are important for the regulation of Tau`s function but an imbalance in PTMs may lead to abnormal Tau function and aggregation. Tau methylation is one of the important PTM of Tau in its physiological state. However, the methylation signature on Tau lysine changes once it acquires pathological aggregated form. Tau methylation can compete with other PTMs such as acetylation and ubiquitination. The state of PTM at these sites determines the fate of Tau protein in terms of its function and stability. The global methylation in neurons, microglia and astrocytes are involved in multiple cellular functions involving their role in epigenetic regulation of gene expression via DNA methylation. Here, we have discussed the effect of methylation on Tau function in a site-specific manner and their cross-talk with other lysine modifications. We have also elaborated the role of methylation in epigenetic aspects and neurodegenerative conditions associated with the imbalance in methylation metabolism affecting global methylation state of cells.

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“…DNA methylation acts as a regulatory mechanism for gene expression, and cell differentiation and various studies have demonstrated the association between change in DNA methylation and disease pathogenesis[ 53 ]. A study by Schlüter et al [ 54 ] compared the genome-wide DNA methylation pattern of unaffected frontal brain white matter of patients with CCALD and AMN with cerebral involvement and found hypermethylation of genes that are majorly involved in differentiation of oligodendrocytes including MBP , CNP , MOG , PLP1 that can result to impaired differentiation of oligodendrocyte precursor cells to remyelinating oligodendrocyte and hypomethylation of genes associated with an immune function such as IFITM1 and CD59 .…”

Section: Potential Modifiers In X-aldmentioning

confidence: 99%

“…These authors also showed that 7α-hydroxycholesterol, 7β-hydroxycholesterol, 7-ketocholesterol, and 9- and 13-hydroxyoctadecadienoic acids were produced as a result of oxidative stress. Increased level of 7-ketocholesterol was found to cause overproduction of free radicles, activation of PRAP-1, and caspase 3 and elevated LC3-II/LC3-I and p62 in BV-12 microglia cells, indicating its ability to induce cell death[ 53 ]. A recent study demonstrated 7-ketocholesterol induced activation of PRAP-1 via NF-κB transforms microglial cells from a resting stage to an active stage, ultimately damaging the neurons.…”

Section: Potential Modifiers In X-aldmentioning

confidence: 99%

Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy

Palakuzhiyil¹,

Christopher²,

Chandra³

2020

WJBC

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X-linked adrenoleukodystrophy (X-ALD), an inborn error of peroxisomal β-oxidation, is caused by defects in the ATP Binding Cassette Subfamily D Member 1 ( ABCD1 ) gene. X-ALD patients may be asymptomatic or present with several clinical phenotypes varying from severe to mild, severe cerebral adrenoleuko-dystrophy to mild adrenomyeloneuropathy (AMN). Although most female heterozygotes present with AMN-like symptoms after 60 years of age, occasional cases of females with the cerebral form have been reported. Phenotypic variability has been described within the same kindreds and even among monozygotic twins. There is no association between the nature of ABCD 1 mutation and the clinical phenotypes, and the molecular basis of phenotypic variability in X-ALD is yet to be resolved. Various genetic, epigenetic, and environmental influences are speculated to modify the disease onset and severity. In this review, we summarize the observations made in various studies investigating the potential modifying factors regulating the clinical manifestation of X-ALD, which could help understand the pathogenesis of the disease and develop suitable therapeutic strategies.

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DNA Methylation in Neurodegenerative Diseases

Cited by 9 publications

References 57 publications

DNA methylation dynamics underlie metamorphic gene regulation programs in Xenopus tadpole brain

DNA methylation dynamics underlie metamorphic gene regulation programs in Xenopus tadpole brain

Methylation as a key regulator of Tau aggregation and neuronal health in Alzheimer’s disease

Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy

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