Ontology highlight
ABSTRACT:
PROVIDER: PRJNA885420 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21753323_1.fastq.gz | Fastqsanger.gz | |||
| SRR21753323_2.fastq.gz | Fastqsanger.gz | |||
| SRR21753324_1.fastq.gz | Fastqsanger.gz | |||
| SRR21753324_2.fastq.gz | Fastqsanger.gz | |||
| SRR21753325_1.fastq.gz | Fastqsanger.gz |
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Project description:Amyotrophic lateral sclerosis (ALS) is frequently driven by GGGGCC short tandem repeat (STR) expansions in C9orf72, yet the mechanisms by which these expansions lead to neurodegeneration remain incompletely understood. Here, we propose a novel mechanism involving higher-order chromatin architecture where C9orf72-STR expansions induce widespread, neuron-specific gains in chromatin loops that are closely linked to transcriptomic dysregulation in ALS. These ectopic loops colocalize with the genomic binding sites of C9orf72-STR RNAs and the architectural protein CTCF, supporting a model in which RNA-DNA interactions promote aberrant loop formation.
2026-02-09 | GSE313074 | GEO
Project description:Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington’s disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation, remain unknown. Here, we demonstrate that Q-rich repeats are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6p (Cyc8p) result in systematic, repeat-length dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6p increases with its repeat number, until a certain threshold where further expansion leads to aggregation. Quantitative proteomic analysis reveals that the Ssn6p repeats affect its solubility and interactions with Tup1 and other regulators. Thus, Q-rich repeats are dynamic functional domains that modulate a regulator’s innate function, with the inherent risk of pathogenic repeat expansions. Transcriptome profiles of two biological replicates of each SSN6 tandem repeat number variant and the WT grown in a glucose-rich medium (4% glucose - glu4) or in a glucose-starved medium (0 % glucose - glu0)
2015-07-01 | E-GEOD-70209 | biostudies-arrayexpress
Project description:In plants, RNA polymerase II (Pol II) transcription of inverted DNA repeats produces hairpin RNAs that are processed by several DICER-LIKE enzymes into siRNAs that are 21-24-nt in length. When targeted to transcriptional regulatory regions, the 24-nt size class can induce RNA-directed DNA methylation (RdDM) and transcriptional gene silencing (TGS). In a forward genetic screen to identify mutants defective in RdDM of a target enhancer leading to TGS of a downstream GFP reporter gene in Arabidopsis thaliana, we recovered a structurally mutated silencer locus, named SM-NM-^T35S, in which the 35S promoter driving transcription of an inverted repeat of target enhancer sequences had been specifically deleted. Although Pol II-dependent, hairpin-derived 21-24-nt siRNAs were no longer generated at the newly created SM-NM-^T35S locus, the GFP reporter gene was nevertheless still partially silenced. Silencing was associated with methylation in a short tandem repeat in the upstream target enhancer and with low levels of 24-nt tandem repeat siRNAs. Introducing an nrpd1 mutation into the SM-NM-^T35S line fully released GFP silencing and eliminated both the tandem repeat methylation and associated 24-nt siRNAs, demonstrating their dependence on Pol IV. Deletion of the 35S promoter thus revealed a Pol IV-dependent pathway of 24-nt siRNA biogenesis that was previously inhibited or masked by the Pol II-dependent pathway in wild-type plants. Both Pol II- and Pol IV-dependent siRNAs accrued predominantly from cytosine (C)-containing segments of the tandem repeat monomer, suggesting that the local base composition influenced siRNA accumulation. Preferential accumulation of siRNAs at C-containing sequences was also observed at an endogenous tandem repeat comprising discrete C-rich and AT-rich sections. Our studies illuminate the potential complexity of siRNA generation at repeat-containing loci and show that Pol IV can act in siRNA biogenesis in the absence of a conventional Pol II promoter. Examination of whole-genome DNA methylation status in transgenic T+S Arabidopsis plant
2013-05-30 | E-GEOD-47453 | biostudies-arrayexpress
Project description:3 to 6% of the human genome is composed of microsatellite sequences, which are short DNA elements composed of 2 to 6 nucleotide motifs repeated in tandem. Expansion of a subset of these microsatellites is the leading cause of >60 diseases. However, most of these mutations are located in sequences annotated as non-coding, thus questioning how they are pathogenic. Here, we found that GGC repeat expansions causing oculopharyngodistal myopathy with or without leukoencephalopathy (OPDM/OPML) are located within previously unrecognized open reading frames (ORFs), resulting in their translation into novel polyglycine-containing proteins. Antibodies developed against these proteins stain the p62-positive inclusions typical of these diseases. Moreover, expression of these polyglycine proteins causes locomotor and skeletal muscle alterations associated with neurodegeneration in cell, fly and mouse models. Finally, we identified a compound, the cationic porphyrin TMPyP4, targeting expression of these polyglycine proteins, raising hope to develop a therapy for these disorders. Overall, this work highlights the complexity and richness of the human genome and the importance of mutations in yet unrecognized small ORFs.
2026-02-03 | PXD071983 | Pride
Project description:Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington’s disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation, remain unknown. Here, we demonstrate that Q-rich repeats are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6p (Cyc8p) result in systematic, repeat-length dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6p increases with its repeat number, until a certain threshold where further expansion leads to aggregation. Quantitative proteomic analysis reveals that the Ssn6p repeats affect its solubility and interactions with Tup1 and other regulators. Thus, Q-rich repeats are dynamic functional domains that modulate a regulator’s innate function, with the inherent risk of pathogenic repeat expansions.
2015-07-01 | GSE70209 | GEO
Project description:Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson’s disease patients, but the association was not found in autopsy confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson’s but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n=354 cases, odds ratio=3.59, p-value=0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.
2019-09-17 | GSE133323 | GEO
Project description:The thymus is a primary lymphoid organ that plays an essential role in T lymphocyte maturation and selection during development of one arm of the mammalian adaptive immune response. Although transcriptional mechanisms have been well documented in thymocyte development, co-/post-transcriptional modifications are also important but have received less attention. Here, we demonstrate that the RNA alternative splicing factor MBNL1, which is sequestered in nuclear RNA foci by C(C)UG short tandem repeat expansions in myotonic dystrophy (DM), is essential for normal thymus development and function. Mbnl1 129S1 knockout mice develop postnatal thymic hyperplasia with thymocyte accumulation. Transcriptome analysis indicates numerous gene expression and RNA mis-splicing events, including transcription factors from the TCF/LEF (T-cell factor/lymphoid enhancer factor) family. CNBP, the gene affected in DM type 2 (DM2), is coordinately expressed with MBNL1 in the developing thymus and DM2 CCTG expansions induce similar transcriptome alterations in DM2 blood, which thus serve as disease-specific biomarkers.
2020-03-05 | GSE138691 | GEO
Project description:Retroelement activation is emerging as a significant factor in the pathogenesis of neurodegenerative diseases. SINE-VNTR-Alu (SVAs) are hominid-specific retroelements that create genetic variation through insertion polymorphisms and variable short tandem repeat (STR) lengths. We investigate how the SVA (CCCTCT)n STR contributes to the striatal neurodegenerative disorder X-linked Dystonia Parkinsonism (XDP), where the repeat expansion length within the pathogenic SVA is inversely correlated with disease onset age. Phenotypic and transcriptomic analysis of XDP and isogenic SVA-deleted striatal organoids revealed that the SVA insertion drives hallmarks of neurodegeneration, including transcriptional dysregulation, decreased neuronal activity, and apoptosis, which are ameliorated by SVA deletion. We identify a (AGAGGG)n hexamer-containing RNA in the SVA that increases expression during organoid maturation and drives R-loop formation in organoids and XDP brain tissue. Knockdown of the (AGAGGG)n hexamer-containing RNA by antisense oligonucleotides rescues apoptosis in the XDP organoids. We demonstrate that a retrotransposon-derived tandem repeat RNA could cause neurodegeneration.
2025-05-17 | GSE289534 | GEO
Project description:A targeted gene panel that covers coding, noncoding, and short tandem repeat regions improves the diagnosis of patients with neurodegenerative diseases
| EGAD00001005114 | EGA