Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

Hamzeiy, Hamid; Savaş, Doruk; Tunca, Ceren; Sen, Nesli Ece; Eken, Aslı Gündoğdu; Şahbaz, Irmak; Calini, Daniela; Tiloca, Cinzia; Ticozzi, Nicola; Silani, Vincenzo; Basak, A. Nazli

doi:10.1159/000486201

Cited by 26 publications

(22 citation statements)

References 88 publications

(96 reference statements)

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“…Although the lack of statistical significance in our study may be the result of the relatively low number of samples and the large number of simultaneously examined CpG sites (27,578), our results are consistent with recent findings showing no change in the overall or global (not site-specific) level of 5-methylcytosine in whole blood from HD patients using an ELISA test ( 30 ), as well as the recent study where the comparison between HD and control cortex samples failed to identify statistically significant differentially methylated regions ( 14 ). Nevertheless, while 5-mC methylation in the cortex was shown to have minimal association with HD status, the study found its level to be associated with age-of-onset ( 14 ).…”

Section: Discussionsupporting

confidence: 91%

“…Plasma homocysteine is responsible for decreased DNA methylase activity, and is an independent risk factor for AD, known to occur at disease onset ( 35 ). Similarly, global DNA methylation in blood was shown in amyotrophic lateral sclerosis ( 30 , 36 ), as well as spinocerebellar ataxias 1 and 2 ( 30 ). However, in Parkinson's disease, similarly to HD, differential DNA methylation of the alfa-synuclein gene was not confirmed in blood ( 37 ), despite being shown to be differentially methylated in brain cells of patients and healthy controls ( 38 ).…”

Section: Discussionmentioning

confidence: 80%

“…In other neurodegenerative disorders, where epigenetic factors are also suggested to play an important role ( 7 , 12 , 30 – 33 ), there have been mixed findings in regard to global differential methylation in whole blood. In Alzheimer's disease (AD), elevated global, not site-specific, DNA methylation has been observed in mononuclear cells from whole blood ( 34 ), and correlated with the up-regulation of plasma homocysteine.…”

Section: Discussionmentioning

confidence: 99%

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DNA Methylation Profiles in Whole Blood of Huntington's Disease Patients

et al. 2018

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Epigenetic mechanisms, especially DNA methylation, are suggested to play a role in the age-of-onset in Huntington's disease (HD) based on studies on patient brains, and cellular and animal models. Methylation is tissue-specific and it is not clear how HD specific methylation in the brain correlates with the blood compartment, which represents a much more clinically accessible sample. Therefore, we explored the presence of HD specific DNA methylation patterns in whole blood on a cohort of HDM and healthy controls from Slovenia. We compared CpG site-specific DNA methylation in whole blood of 11 symptomatic and 9 pre-symptomatic HDM (HDM), and 15 healthy controls, by using bisulfite converted DNA on the Infinium® Human Methylation27 BeadChip microarray (Illumina) covering 27,578 CpG sites and 14,495 genes. Of the examined 14,495 genes, 437 were differentially methylated (p < 0.01) in pre-symptomatic HDM compared to controls, with three genes (CLDN16, DDC, NXT2) retaining statistical significance after the correction for multiple testing (false discovery rate, FDR < 0.05). Comparisons between symptomatic HDM and controls, and the comparison of symptomatic and pre-symptomatic HDM further identified 260 and 198 differentially methylated genes (p < 0.01), respectively, whereas the comparison of all HDM (symptomatic and pre-symptomatic) and healthy controls identified 326 differentially methylated genes (p < 0.01), however, none of these changes retained significance (FDR < 0.05) after the correction for multiple testing. The results of our study suggest that methylation signatures in the blood compartment are not robust enough to prove as valuable biomarkers for predicting HD progression, but recognizable changes in methylation deserve further research.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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DNA Methylation Profiles in Whole Blood of Huntington's Disease Patients

et al. 2018

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“…The output counts were used as a score to denote the strength of the evidence for each gene with ALS in GeneRIF and DisGeNet databases (Table A2). (Hamzeiy et al, 2018).…”

Section: Gene Coexpression Network Analysismentioning

confidence: 99%

Revisiting the complex architecture of ALS in Turkey: Expanding genotypes, shared phenotypes, molecular networks, and a public variant database

et al. 2020

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The last decade has proven that amyotrophic lateral sclerosis (ALS) is clinically and genetically heterogeneous, and that the genetic component in sporadic cases might be stronger than expected. This study investigates 1,200 patients to revisit ALS in the ethnically heterogeneous yet inbred Turkish population. Familial ALS (fALS) accounts for 20% of our cases. The rates of consanguinity are 30% in fALS and 23% in sporadic ALS (sALS). Major ALS genes explained the disease cause in only 35% of fALS, as compared with ~70% in Europe and North America. Whole exome sequencing resulted in a discovery rate of 42% (53/127). Whole genome analyses in 623 sALS cases and 142 population controls, sequenced within Project MinE, revealed well‐established fALS gene variants, solidifying the concept of incomplete penetrance in ALS. Genome‐wide association studies (GWAS) with whole genome sequencing data did not indicate a new risk locus. Coupling GWAS with a coexpression network of disease‐associated candidates, points to a significant enrichment for cell cycle‐ and division‐related genes. Within this network, literature text‐mining highlights DECR1, ATL1, HDAC2, GEMIN4, and HNRNPA3 as important genes. Finally, information on ALS‐related gene variants in the Turkish cohort sequenced within Project MinE was compiled in the GeNDAL variant browser (http://www.gendal.org).

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“…Recently, elevated global DNA ME was observed in SCA 1 and 2 [111]. In a SCA7 mouse model, CCCTCbinding factor (CTCF) acts as a trans-acting factor that interacts in a ME-dependent manner with the adjacent cis-environment to prevent expansion of CAG repeat [112].…”

Section: Epigenetic Factorsmentioning

confidence: 99%

DNA repair in trinucleotide repeat ataxias

et al. 2018

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The inherited cerebellar ataxias comprise of a genetic heterogeneous group of disorders. Pathogenic expansions of cytosine-adenine-guanine (CAG) encoding polyglutamine tracts account for the largest proportion of autosomal dominant cerebellar ataxias, while GAA expansion in the first introns of frataxin gene is the commonest cause of autosomal recessive cerebellar ataxias. Currently, there is no available treatment to alter the disease trajectory, with devastating consequences for affected individuals. Inter- and Intrafamily phenotypic variability suggest the existence of genetic modifiers, which may become targets amendable to treatment. Recent studies have demonstrated the importance of DNA repair pathways in modifying spinocerebellar ataxia with CAG repeat expansions. In this review, we discuss the mechanisms in which DNA repair pathways, epigenetics and other genetic factors may act as modifiers in cerebellar ataxias due to trinucleotide repeat expansions.

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Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

Cited by 26 publications

References 88 publications

DNA Methylation Profiles in Whole Blood of Huntington's Disease Patients

DNA Methylation Profiles in Whole Blood of Huntington's Disease Patients

Revisiting the complex architecture of ALS in Turkey: Expanding genotypes, shared phenotypes, molecular networks, and a public variant database

DNA repair in trinucleotide repeat ataxias

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