Homo sapiens
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-5040
PROVIDER: PRJNA96673 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The inherited neurodegenerative disease Friedreich’s ataxia (FRDA) is caused by hyperexpansion of GAA•TTC trinucleotide repeats within the first intron of the FXN gene, encoding the mitochondrial protein frataxin. Long GAA•TTC repeats causes heterochromatin-mediated silencing and loss of frataxin in affected individuals. We report the derivation of induced pluripotent stem cells (iPSCs) from FRDA patient fibroblasts through retroviral transduction of transcription factors. FXN gene repression is maintained in the iPSCs, as are the mRNA and miRNA global expression signatures reflecting the human disease. GAA•TTC repeats uniquely in FXN in the iPSCs exhibit repeat instability similar to patient families, where they expand and/or contract with discrete changes in length between generations. The mismatch repair enzyme Msh2, implicated in repeat instability in other triplet repeat diseases, is highly expressed in the iPSCs, occupies FXN intron 1, and shRNA silencing of Msh2 impedes repeat expansion, providing a possible molecular explanation for repeat expansion in FRDA.
2010-07-02 | GSE22651 | GEO
Project description:Expansion of triplex-forming GAA/TTC repeats in the first intron of FRDA gene is known to cause Friedreich’s ataxia. Besides FRDA, there are a number of other highly polymorphic GAA/TTC loci in the human genome where the size variations so far were considered to be a neutral event. Using yeast as a model system, we demonstrate that expanded GAA/TTC repeats represent a threat to eukaryotic genome integrity by triggering double-strand breaks and gross chromosomal rearrangements. The fragility potential strongly depends on the length of the track and orientation of the repeats relative to the replication origin which correlates with their propensity to adopt secondary structure and to block replication progression. We show that fragility is mediated by mismatch repair machinery and requires the MutS(beta) and endonuclease activity of MutL(alpha). We suggest that the mechanism of GAA/TTC-induced chromosome aberrations defined in yeast can also operate in human carriers with expanded tracks. Keywords: CGH-array
2008-05-14 | GSE11425 | GEO
Project description:Expansion of triplex-forming GAA/TTC repeats in the first intron of FRDA gene is known to cause Friedreich’s ataxia. Besides FRDA, there are a number of other highly polymorphic GAA/TTC loci in the human genome where the size variations so far were considered to be a neutral event. Using yeast as a model system, we demonstrate that expanded GAA/TTC repeats represent a threat to eukaryotic genome integrity by triggering double-strand breaks and gross chromosomal rearrangements. The fragility potential strongly depends on the length of the track and orientation of the repeats relative to the replication origin which correlates with their propensity to adopt secondary structure and to block replication progression. We show that fragility is mediated by mismatch repair machinery and requires the MutS(beta) and endonuclease activity of MutL(alpha). We suggest that the mechanism of GAA/TTC-induced chromosome aberrations defined in yeast can also operate in human carriers with expanded tracks. Keywords: CGH-array Genomic DNA from each of 15 strains was competitively hybridized to DNA from the parent diploid strain (Cy3/green). Gains of genomic segments in the survivors were detected as continuous regions of positive Log2 Red:Green ratios, while losses were detected as negative Log2 Red:Green ratios.
2008-05-14 | E-GEOD-11425 | biostudies-arrayexpress
Project description:Friedreich’s Ataxia Induced Pluripotent Stem Cells Recapitulate GAA•TTC Triplet-Repeat Instability
| PRJNA128015 | ENA
Project description:Lymphoblast cells from a patient with Freidriech's Ataxia were incubated with pyrrole-imidazole polyamides targeted to the GAA triplet repeat in the intron 1. The polyamides were shown in cell culture to increase levels of endogenous frataxin mRNA. A normal sibling derived lymphoblast cell line was used as a control. Keywords: human lymphoblast cells
2006-06-14 | GSE5040 | GEO
Project description:Switching a paused RNA polymerase II into productive elongation is tightly-regulated, especially at genes involved in human development and disease. To exert control on this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that binds a component of the transcription elongation machinery. The resultant bifunctional molecules convert constituent modules from broad-spectrum inhibitors of transcription into a gene-specific stimulator of transcriptional elongation. Here, we present Syn-TEF1, a molecule that actively facilitates transcription across repressive GAA repeats that silence frataxin expression in Friedreich’s ataxia, a debilitating and ultimately lethal neurodegenerative disease with no effective therapy.
2017-12-06 | GSE99402 | GEO
Project description:Switching a paused RNA polymerase II into productive elongation is tightly-regulated, especially at genes involved in human development and disease. To exert control on this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that binds a component of the transcription elongation machinery. The resultant bifunctional molecules convert constituent modules from broad-spectrum inhibitors of transcription into a gene-specific stimulator of transcriptional elongation. Here, we present Syn-TEF1, a molecule that actively facilitates transcription across repressive GAA repeats that silence frataxin expression in Friedreich’s ataxia, a debilitating and ultimately lethal neurodegenerative disease with no effective therapy.
2017-12-06 | GSE99400 | GEO
Project description:Lymphoblast cells from a patient with Freidriech's Ataxia were incubated with pyrrole-imidazole polyamides targeted to the GAA triplet repeat in the intron 1. The polyamides were shown in cell culture to increase levels of endogenous frataxin mRNA. A normal sibling derived lymphoblast cell line was used as a control. Experiment Overall Design: Normal (GM15851) and patient (GM15850) cell lines were incubated in the presence of match polyamide FA1 at 1uM, 2uM or mismatch polyamide FA2 at 2uM for 7days prior to RNA purification and microarray analysis.
2008-06-13 | E-GEOD-5040 | biostudies-arrayexpress
Project description:The inherited neurodegenerative disease Friedreichâ??s ataxia (FRDA) is caused by hyperexpansion of GAAâ?¢TTC trinucleotide repeats within the first intron of the FXN gene, encoding the mitochondrial protein frataxin. Long GAAâ?¢TTC repeats causes heterochromatin-mediated silencing and loss of frataxin in affected individuals. We report the derivation of induced pluripotent stem cells (iPSCs) from FRDA patient fibroblasts through retroviral transduction of transcription factors. FXN gene repression is maintained in the iPSCs, as are the mRNA and miRNA global expression signatures reflecting the human disease. GAAâ?¢TTC repeats uniquely in FXN in the iPSCs exhibit repeat instability similar to patient families, where they expand and/or contract with discrete changes in length between generations. The mismatch repair enzyme Msh2, implicated in repeat instability in other triplet repeat diseases, is highly expressed in the iPSCs, occupies FXN intron 1, and shRNA silencing of Msh2 impedes repeat expansion, providing a possible molecular explanation for repeat expansion in FRDA. 65 samples from various number of tissue, primary cell lines undifferenatiated human embryonic stem cell lines, induces pluripotent stem cell lines have been run on Illumina HT12 v3 chips.
2010-07-30 | E-GEOD-22651 | biostudies-arrayexpress
Project description:Background: Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein. All Friedreich ataxia patients carry a GAA/TTC repeat expansion in the first intron of the frataxin gene, either in the homozygous state or in compound heterozygosity with other loss-of-function mutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreich ataxia patients, including increased trimethylation of histone H3 at lysine 9 and hypoacetylation of histones H3 and H4. Methodology/Principal Findings: By chromatin immunoprecipitation, we detected the same heterochromatin marks in homozygous mice carrying a (GAA)230 repeat in the first intron of the mouse frataxin gene (KIKI mice). These animals have decreased frataxin levels and, by microarray analysis, show significant gene expression changes in several tissues. We treated KIKI mice with a novel histone deacetylase inhibitor, compound 106, which substantially increases frataxin mRNA levels in cells from Friedreich ataxia individuals. Treatment increased histone H3 and H4 acetylation in chromatin near the GAA repeat and restored wild-type frataxin levels in the nervous system and heart, as determined by quantitative RT-PCR and semiquantitative western blot analysis. No toxicity was observed. Furthermore, most of the differentially expressed genes in KIKI mice reverted towards wild-type levels. Conclusions/Significance: Lack of acute toxicity, normalization of frataxin levels and of the transcription profile changes resulting from frataxin deficiency provide strong support to a possible efficacy of this or related compounds in reverting the pathological process in Friedreich ataxia, a so far incurable neurodegenerative disease. Keywords: drug response
2008-03-08 | GSE10745 | GEO