DNA methylation and trinucleotide repeat expansion diseases

Copyright @ 2012 InTechThis article has been made available through the Brunel Open Access Publishing Fund.This article is made available through the Brunel Open Access Publishing Fund

DNA methylation and trinucleotide repeat expansion diseases

Copyright @ 2012 InTechThis article has been made available through the Brunel Open Access Publishing Fund.This article is made available through the Brunel Open Access Publishing Fund

Comparative (computational) analysis of the DNA methylation status of trinucleotide repeat expansion diseases

Copyright © 2013 Mohammadmersad Ghorbani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been made available through the Brunel Open Access Publishing Fund.Previous studies have examined DNA methylation in different trinucleotide repeat diseases. We have combined this data and used a pattern searching algorithm to identify motifs in the DNA surrounding aberrantly methylated CpGs found in the DNA of patients with one of the three trinucleotide repeat (TNR) expansion diseases: fragile X syndrome (FRAXA), myotonic dystrophy type I (DM1), or Friedreich’s ataxia (FRDA). We examined sequences surrounding both the variably methylated (VM) CpGs, which are hypermethylated in patients compared with unaffected controls, and the nonvariably methylated CpGs which remain either always methylated (AM) or never methylated (NM) in both patients and controls. Using the J48 algorithm of WEKA analysis, we identified that two patterns are all that is necessary to classify our three regions CCGG* which is found in VM and not in AM regions and AATT* which distinguished between NM and VM + AM using proportional frequency. Furthermore, comparing our software with MEME software, we have demonstrated that our software identifies more patterns than MEME in these short DNA sequences. Thus, we present evidence that the DNA sequence surrounding CpG can influence its susceptibility to be de novo methylated in a disease state associated with a trinucleotide repeat.European Union Seventh Framework Programme and The Brunel University Graduate Program

The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues

Friedreich ataxia (FRDA) is caused by a homozygous GAA repeat expansion mutation within intron 1 of the FXN gene, leading to reduced expression of frataxin protein. Evidence suggests that the mutation may induce epigenetic changes and heterochromatin formation, thereby impeding gene transcription. In particular, studies using FRDA patient blood and lymphoblastoid cell lines have detected increased DNA methylation of specific CpG sites upstream of the GAA repeat and histone modifications in regions flanking the GAA repeat. In this report we show that such epigenetic changes are also present in FRDA patient brain, cerebellum and heart tissues, the primary affected systems of the disorder. Bisulfite sequence analysis of the FXN flanking GAA regions reveals a shift in the FRDA DNA methylation profile, with upstream CpG sites becoming consistently hypermethylated and downstream CpG sites becoming consistently hypomethylated. We also identify differential DNA methylation at three specific CpG sites within the FXN promoter and one CpG site within exon 1. Furthermore, we show by chromatin immunoprecipitation (ChIP) analysis that there is overall decreased histone H3K9 acetylation together with increased H3K9 methylation of FRDA brain tissue. Further studies of brain, cerebellum and heart tissues from our GAA repeat expansion-containing FRDA YAC transgenic mice reveal comparable epigenetic changes to those detected in FRDA patient tissue. We have thus developed a mouse model that will be a valuable resource for future therapeutic studies targeting epigenetic modifications of the FXN gene to increase frataxin expression

Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in ataxin-3 (SCA3, MJD1) protein. In biochemical experiments we demonstrate that mutant SCA3exp specifically associated with the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1), an intracellular calcium (Ca2+) release channel. In electrophysiological and Ca2+ imaging experiments we show that InsP3R1 are sensitized to activation by InsP3 in the presence of mutant SCA3exp. We found that feeding SCA3-YAC-84Q transgenic mice with dantrolene, a clinically relevant stabilizer of intracellular Ca2+ signaling, improved their motor performance and prevented neuronal cells loss in pontine nuclei and substantia nigra regions. Our results indicate that deranged Ca2+ signaling may play an important role in SCA3 pathology and that Ca2+ signaling stabilizers such as dantrolene may be considered as potential therapeutic drugs for treatment of SCA3 patients

The mismatch repair system protects against intergenerational GAA repeat instability in a Friedreich ataxia mouse model

Copyright @ 2012 Elsevier. The article can be accessed from the link below.This article has been made available through the Brunel Open Access Publishing Fund.Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a dynamic GAA repeat expansion mutation within intron 1 of the FXN gene. Studies of mouse models for other trinucleotide repeat (TNR) disorders have revealed an important role of mismatch repair (MMR) proteins in TNR instability. To explore the potential role of MMR proteins on intergenerational GAA repeat instability in FRDA, we have analyzed the transmission of unstable GAA repeat expansions from FXN transgenic mice which have been crossed with mice that are deficient for Msh2, Msh3, Msh6 or Pms2. We find in all cases that absence of parental MMR protein not only maintains transmission of GAA expansions and contractions, but also increases GAA repeat mutability (expansions and/or contractions) in the offspring. This indicates that Msh2, Msh3, Msh6 and Pms2 proteins are not the cause of intergenerational GAA expansions or contractions, but act in their canonical MMR capacity to protect against GAA repeat instability. We further identified differential modes of action for the four MMR proteins. Thus, Msh2 and Msh3 protect against GAA repeat contractions, while Msh6 protects against both GAA repeat expansions and contractions, and Pms2 protects against GAA repeat expansions and also promotes contractions. Furthermore, we detected enhanced occupancy of Msh2 and Msh3 proteins downstream of the FXN expanded GAA repeat, suggesting a model in which Msh2/3 dimers are recruited to this region to repair mismatches that would otherwise produce intergenerational GAA contractions. These findings reveal substantial differences in the intergenerational dynamics of expanded GAA repeat sequences compared with expanded CAG/CTG repeats, where Msh2 and Msh3 are thought to actively promote repeat expansions.This study is funded under European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement number 242193/EFACTS. This article is made available through the Brunel Open Access Publishing Fund

Correlation of eigenstates in the critical regime of quantum Hall systems

We extend the multifractal analysis of the statistics of critical wave functions in quantum Hall systems by calculating numerically the correlations of local amplitudes corresponding to eigenstates at two different energies. Our results confirm multifractal scaling relations which are different from those occurring in conventional critical phenomena. The critical exponent corresponding to the typical amplitude, $\alpha_0\approx 2.28$, gives an almost complete characterization of the critical behavior of eigenstates, including correlations. Our results support the interpretation of the local density of states being an order parameter of the Anderson transition.Comment: 17 pages, 9 Postscript figure

Universal Multifractality in Quantum Hall Systems with Long-Range Disorder Potential

We investigate numerically the localization-delocalization transition in quantum Hall systems with long-range disorder potential with respect to multifractal properties. Wavefunctions at the transition energy are obtained within the framework of the generalized Chalker--Coddington network model. We determine the critical exponent $\alpha_0$ characterizing the scaling behavior of the local order parameter for systems with potential correlation length $d$ up to $12$ magnetic lengths $l$. Our results show that $\alpha_0$ does not depend on the ratio $d/l$. With increasing $d/l$, effects due to classical percolation only cause an increase of the microscopic length scale, whereas the critical behavior on larger scales remains unchanged. This proves that systems with long-range disorder belong to the same universality class as those with short-range disorder.Comment: 4 pages, 2 figures, postsript, uuencoded, gz-compresse

Multifractal properties of critical eigenstates in two-dimensional systems with symplectic symmetry

The multifractal properties of electronic eigenstates at the metal-insulator transition of a two-dimensional disordered tight-binding model with spin-orbit interaction are investigated numerically. The correlation dimensions of the spectral measure $\widetilde{D}_{2}$ and of the fractal eigenstate $D_{2}$ are calculated and shown to be related by $D_{2}=2\widetilde{D}_{2}$. The exponent $\eta=0.35\pm 0.05$ describing the energy correlations of the critical eigenstates is found to satisfy the relation $\eta=2-D_{2}$.Comment: 6 pages RevTeX; 3 uuencoded, gzipped ps-figures to appear in J. Phys. Condensed Matte

Surface Morphology and Strain Relief in Surfactant Mediated Growth of Germanium on Silicon (111)

The growth of Ge on Si is strongly modified by adsorbates called surfactants. The relevance of the stress on surface morphology and the growth mode of Ge on Si(111) is presented in a detailed in situ study by high resolution low energy electron diffraction (LEED) during the deposition. The change from islanding to layer-by-layer growth mode is seen in the oscillatory intensity behaviour of the 00-spot. As a strain relief mechanism, the Ge-film forms a microscopic rough surface of small triangular and defect-free pyramids in the pseudomorphic growth regime up to 8 monolayers. As soon as the pyramids are completed and start to coalesce, strain relieving defects are created at their base, finally arranging to the dislocation network. Without the driving force for the micro-roughness, the stress, the surface flattens again showing a much larger terrace length. The formation process of the dislocation network results in a spot splitting in LEED, since the periodic dislocations at the interface give rise to elastic deformation of the surface. Surprisingly the Ge-film is relaxed to 70% immediately after 8 monolayers of coverage, which is attributed to the micro rough surface morphology, providing innumerous nucleation sites for dislocation