Comparative (Computational) Analysis of the DNA Methylation Status of Trinucleotide Repeat Expansion Diseases

Ghorbani, Mohammadmersad; Taylor, Simon J. E.; Pook, Mark A.; Payne, Annette

doi:10.1155/2013/689798

Cited by 12 publications

(7 citation statements)

References 38 publications

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“…Congenital DM1, but not DM2 myoblasts show differentiation defects ( 66 , 67 ). There are also changes in epigenetic marks in both DM1 and DM2 patient cells, suggesting possible changes to genome organization: DM2 myoblasts exhibit heterochromatin accumulation ( 68 ) and the DM1 locus is methylated to varying degrees across the expanded repeats ( 69 ) and especially in congenital samples ( 70 ).…”

Section: Dm—accelerated Aging At the Molecular Level?mentioning

confidence: 99%

Myotonic Dystrophy—A Progeroid Disease?

et al. 2018

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Myotonic dystrophies (DM) are slowly progressing multisystemic disorders caused by repeat expansions in the DMPK or CNBP genes. The multisystemic involvement in DM patients often reflects the appearance of accelerated aging. This is partly due to visible features such as cataracts, muscle weakness, and frontal baldness, but there are also less obvious features like cardiac arrhythmia, diabetes or hypogammaglobulinemia. These aging features suggest the hypothesis that DM could be a segmental progeroid disease. To identify the molecular cause of this characteristic appearance of accelerated aging we compare clinical features of DM to “typical” segmental progeroid disorders caused by mutations in DNA repair or nuclear envelope proteins. Furthermore, we characterize if this premature aging effect is also reflected on the cellular level in DM and investigate overlaps with “classical” progeroid disorders. To investigate the molecular similarities at the cellular level we use primary DM and control cell lines. This analysis reveals many similarities to progeroid syndromes linked to the nuclear envelope. Our comparison on both clinical and molecular levels argues for qualification of DM as a segmental progeroid disorder.

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Section: Dm—accelerated Aging At the Molecular Level?mentioning

confidence: 99%

Myotonic Dystrophy—A Progeroid Disease?

et al. 2018

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“…Although epigenetic modifications in DM-affected satellite cells have not yet been studied specifically, triplet expansions seem to induce different DNA methylation patterns. In this regard, the DMPK locus shows a variably methylated sequence upstream of the triplet expansion, whereas this sequence is unmethylated in healthy controls (Ghorbani et al, 2013 ). Interestingly, the expanded sequence and the downstream sequence are not methylated (López Castel et al, 2011 ).…”

Section: Epigenetic Modifications In Dms and Agingmentioning

confidence: 99%

Muscle wasting in myotonic dystrophies: a model of premature aging

Mateos-Aierdi

Goicoechea

Aiastui

et al. 2015

Front. Aging Neurosci.

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Myotonic dystrophy type 1 (DM1 or Steinert’s disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3′ untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9 (CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.

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“…This ability proved critical for reducing assignation errors [ 66 ]. It is very popular and was used in studies as diverse as epilepsy characterization using imaging data [ 67 ] and methylated DNA patterns linked to genetic diseases [ 68 ]. Its swiftness enables to implement it in parallel on different type of data, so that complete annotation of very large dataset can be reached in a timeframe of one minute.…”

Section: Introductionmentioning

confidence: 99%

Genomics and Machine Learning for Taxonomy Consensus: The Mycobacterium tuberculosis Complex Paradigm

et al. 2015

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Infra-species taxonomy is a prerequisite to compare features such as virulence in different pathogen lineages. Mycobacterium tuberculosis complex taxonomy has rapidly evolved in the last 20 years through intensive clinical isolation, advances in sequencing and in the description of fast-evolving loci (CRISPR and MIRU-VNTR). On-line tools to describe new isolates have been set up based on known diversity either on CRISPRs (also known as spoligotypes) or on MIRU-VNTR profiles. The underlying taxonomies are largely concordant but use different names and offer different depths. The objectives of this study were 1) to explicit the consensus that exists between the alternative taxonomies, and 2) to provide an on-line tool to ease classification of new isolates. Genotyping (24-VNTR, 43-spacers spoligotypes, IS6110-RFLP) was undertaken for 3,454 clinical isolates from the Netherlands (2004-2008). The resulting database was enlarged with African isolates to include most human tuberculosis diversity. Assignations were obtained using TB-Lineage, MIRU-VNTRPlus, SITVITWEB and an algorithm from Borile et al. By identifying the recurrent concordances between the alternative taxonomies, we proposed a consensus including 22 sublineages. Original and consensus assignations of the all isolates from the database were subsequently implemented into an ensemble learning approach based on Machine Learning tool Weka to derive a classification scheme. All assignations were reproduced with very good sensibilities and specificities. When applied to independent datasets, it was able to suggest new sublineages such as pseudo-Beijing. This Lineage Prediction tool, efficient on 15-MIRU, 24-VNTR and spoligotype data is available on the web interface “TBminer.” Another section of this website helps summarizing key molecular epidemiological data, easing tuberculosis surveillance. Altogether, we successfully used Machine Learning on a large dataset to set up and make available the first consensual taxonomy for human Mycobacterium tuberculosis complex. Additional developments using SNPs will help stabilizing it.

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Comparative (Computational) Analysis of the DNA Methylation Status of Trinucleotide Repeat Expansion Diseases

Cited by 12 publications

References 38 publications

Myotonic Dystrophy—A Progeroid Disease?

Myotonic Dystrophy—A Progeroid Disease?

Muscle wasting in myotonic dystrophies: a model of premature aging

Genomics and Machine Learning for Taxonomy Consensus: The Mycobacterium tuberculosis Complex Paradigm

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