Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity

Zheleznyakova, Galina Yurevna; Voisin, Sarah; Kiselev, Anton; Almén, Markus Sällman; Xavier, Miguel J; Maretina, Marianna; Tishchenko, L. I.; Fredriksson, Robert; Baranov, V. S.; Schiöth, Helgi B.

doi:10.1038/ejhg.2012.293

Cited by 33 publications

(40 citation statements)

References 58 publications

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“…For example, the methylation of other genes, such as CHML, ARHGAP22, CYTSB, CDK2AP1, and SLC23A2, also contributes to the SMA phenotype modification (Zheleznyakova et al, 2013). SMA clinicopathology may also be affected by other epigenetic modifications such as acetylation.…”

Section: Discussionmentioning

confidence: 99%

Association between SMN2 methylation and disease severity in Chinese children with spinal muscular atrophy

Cao

et al. 2016

J. Zhejiang Univ. Sci. B

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Abstract:The homozygous loss of the survival motor neuron 1 (SMN1) gene is the primary cause of spinal muscular atrophy (SMA), a neuromuscular degenerative disease. A genetically similar gene, SMN2, which is not functionally equivalent in all SMA patients, modifies the clinical SMA phenotypes. We analyzed the methylation levels of 4 CpG islands (CGIs) in SMN2 in 35 Chinese children with SMA by MassARRAY. We found that three CpG units located in CGI 1 (nucleotides (nt) −871, −735) and CGI 4 (nt +999) are significantly hypomethylated in SMA type III compared with type I or II children after receiving Bonferroni correction. In addition to the differentially methylated CpG unit of nt −871, the methylation level of the nt −290/−288/−285 unit was negatively correlated with the expression of SMN2 full-length transcripts (SMN2-fl). In addition, the methylation level at nt +938 was inversely proportional to the ratio of SMN2-fl and lacking exon 7 transcripts (SMN2-7, fl/7), and was not associated with the SMN2 transcript levels. Thus, we can conclude that SMN2 methylation may regulate the SMA disease phenotype by modulating its transcription.

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Section: Discussionmentioning

confidence: 99%

Association between SMN2 methylation and disease severity in Chinese children with spinal muscular atrophy

Cao

et al. 2016

J. Zhejiang Univ. Sci. B

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“…It should be noted that the cascade of actin remod eling also suffers in SMA, a neurodegenerative disease in newborns and children [62]. Genome wide methy lation analysis in patients with SMA, as compared with healthy people, found significant differences in the level of methylation of CpG sites in 40 genes.…”

Section: Neuroepigenetics: Genetic Diseases and Syndromes With Multipmentioning

confidence: 98%

“…With the database String 9.05, it was found that the CHML gene product, REP2, interacts with Rab5A, Rab3A, RablA, and Rab6A GTPases and that the protein ARHGAP22 interacts with RhoB, RhoD, RhoF, RhoG, RhoH, RhoU, and RhoQ GTPases (string db.org, medium confidence score 0.400) [62].…”

Section: Neuroepigenetics: Genetic Diseases and Syndromes With Multipmentioning

confidence: 99%

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Neurogenetics and neuroepigenetics

2015

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Behavioral genetics or "Neurogenetics," is based on the evolutionary ideas of T. Dobzhansky on brain development and behavior. It continues with the "experimental genetics of higher nervous activity" of I. Pavlov and uses a comparative approach in the study of heredity and variation in behavioral manifestations, from Protozoa to humans. The study of the classical Pavlovian conditioned reflex in mutant Drosophila helped to identify the main types of memory and their evolutionary conservatism. Long term memory defects are caused by mutations of the same genes as in mental retardation in humans, when signaling cascades inter secting with the cAMP dependent pathway are damaged. The cascade of actin remodeling is also among these. The key enzyme, LIM kinase 1, controls cognitive manifestations of the "genomic disease" Williams deletion syndrome. Its study resulted in the recognition of neuroepigenetics as an interface between the genome and environmental influences. Epigenetic factors of "variability"-DNA methylation, histone acetylation, and miRNA regulation-do not change the structure of the gene but its manifestations. Certain miRNAs have already been considered to be both biomarkers for neurodegenerative diseases and factors of the transgenerational transmission of the behaviorial properties of ancestors who experienced stress from adverse environmental influences.

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“…The correct DNA methylation patterns provide regulation of cell type-specific gene expression by affecting the capacity of DNA to interact with transcription factors and methyl-CpG-binding proteins (Doerfler 1981, Razin & Cedar 1991, Zou et al 2012). Numerous studies discuss the possible role of the altered DNA methylation patterns in the initiation and progression of various pathologies, including developmental failures (Shi & Haaf 2002, Pliushch et al 2010, Ehrlich & Lacey 2013, Shubina et al 2013, Skryabin et al 2013, Zheleznyakova et al 2013, Luo et al 2014, Pendina et al 2014.…”

Section: Introductionmentioning

confidence: 99%

Chromosome hydroxymethylation patterns in human zygotes and cleavage-stage embryos

Efimova¹,

Pendina²,

Tikhonov³

et al. 2015

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We report the sequential changes in 5-hydroxymethylcytosine (5hmC) patterns in the genome of human preimplantation embryos during DNA methylation reprogramming. We have studied chromosome hydroxymethylation and methylation patterns in triploid zygotes and blastomeres of cleavage-stage embryos. Using indirect immunofluorescence, we have analyzed the localization of 5hmC and its co-distribution with 5-methylcytosine (5mC) on the QFH-banded metaphase chromosomes. In zygotes, 5hmC accumulates in both parental chromosome sets, but hydroxymethylation is more intensive in the poorly methylated paternal set. In the maternal set, chromosomes are highly methylated, but contain little 5hmC. Hydroxymethylation is highly region specific in both parental chromosome sets: hydroxymethylated loci correspond to R-bands, but not G-bands, and have well-defined borders, which coincide with the R/G-band boundaries. The centromeric regions and heterochromatin at 1q12, 9q12, 16q11.2, and Yq12 contain little 5mC and no 5hmC. We hypothesize that 5hmC may mark structural/functional genome 'units' corresponding to chromosome bands in the newly formed zygotic genome. In addition, we suggest that the hydroxymethylation of R-bands in zygotes can be treated as a new characteristic distinguishing them from G-bands. At cleavages, chromosomes with asymmetrical hydroxymethylation of sister chromatids appear. They decrease in number during cleavages, whereas totally non-hydroxymethylated chromosomes become numerous. Taken together, our findings suggest that, in the zygotic genome, 5hmC is distributed selectively and its pattern is determined by both parental origin of chromosomes and type of chromosome bands -R, G, or C. At cleavages, chromosome hydroxymethylation pattern is dynamically changed due to passive and non-selective overall loss of 5hmC, which coincides with that of 5mC.

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Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity

Cited by 33 publications

References 58 publications

Association between SMN2 methylation and disease severity in Chinese children with spinal muscular atrophy

Association between SMN2 methylation and disease severity in Chinese children with spinal muscular atrophy

Neurogenetics and neuroepigenetics

Chromosome hydroxymethylation patterns in human zygotes and cleavage-stage embryos

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