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Genetics, Cellular and Natural History of X-Linked Dystonia Parkinsonism

ABSTRACT: Genetics, Cellular and Natural History of X-Linked Dystonia Parkinsonism

PROVIDER: PRJNA430957 | ENA |

REPOSITORIES: ENA

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Genetics, Cellular and Natural History of X-Linked Dystonia Parkinsonism

Project description:Genetics, Cellular and Natural History of X-Linked Dystonia Parkinsonism

| PRJNA430958 | ENA

G-quadruplexes within the SVA retrotransposon modulate TAF1 gene expression in X-linked Dystonia Parkinsonism [RNA-Seq]

Project description:X-linked dystonia parkinsonism (XDP) is an inherited neurodegenerative disease characterized by the antisense insertion of an SVA retrotransposon into the TAF1 gene, encoding for the largest subunit of the basal transcription factor TFIID, which is essential for RNA polymerase II activity. This SVA insertion has been associated with altered TAF1 expression levels, but the cause of this outcome and its link to the development of XDP remain unknown. Unique to the XDP SVA compared to other SVA retrotransposons in the human genome is the amplification of the (GGGAGA)n repeat domain, creating a unique G4-prone region, whose length correlates with age at onset and disease severity. By ChIP-seq and ChIP-qPCR with the anti-G4 antibody BG4, we assessed that G4s are present in the folded state in the XDP SVA of these cells. Using available G4 ligands, we demonstrated that stabilization of the XDP SVA G4s reduces TAF1 transcripts in the exons around and downstream of the SVA, while increasing the transcription of the upstream exons, possibly through a positive feedback loop.

2024-09-04 | GSE250293 | GEO

G-quadruplexes within the SVA retrotransposon modulate TAF1 gene expression in X-linked Dystonia Parkinsonism

Project description:G-quadruplexes within the SVA retrotransposon modulate TAF1 gene expression in X-linked Dystonia Parkinsonism

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SRRM4/nSR100 directs neuronal-specific microexon splicing of TAF1 mRNA involved in X-linked Dystonia-Parkinsonism

Project description:X-linked dystonia-parkinsonism is a neurodegenerative disease, which is caused by a SVA retrotransposon insertion within TAF1, gene encoding an integral component of the basal transcription factor TFIID. The SVA insertion has been shown to induce defects both in biosynthesis and in alternative splicing of TAF1 mRNA in various cell types. This includes the reduction of a neuron-specific isoform of TAF1 mRNA generated by inclusion of the evolutionary conserved microexon 34’ (TAF1-34’). In this study, we investigated the tissue distribution of TAF1-34’ mRNA and protein and the neuron-specific mechanism sustaining its alternative splicing. Using isoform-specific RNA probes and antibodies, we observe that canonical TAF1 and TAF1-34’ have different distributions in the brain. To our knowledge, this is the first in situ detection of a microexon. We find that the differential expression of these two isoforms distinguishes proliferating from post-mitotic neurons in vitro and in vivo. Knockdown and ectopic expression experiments in cell lines demonstrated that the neuron-specific splicing factor nSR100/SRRM4 is directing the inclusion of microexon 34’ into TAF1 mRNA. These results show that SRRM4 regulates temporal and spatial distribution of alternative TAF1 mRNAs to generate a neuron-specific isoform of basal transcription factor TFIID.

2020-05-26 | PXD009905 | Pride

G-quadruplexes within the SVA retrotransposon modulate TAF1 gene expression in X-linked Dystonia Parkinsonism [RNA-Seq]

Project description:G-quadruplexes within the SVA retrotransposon modulate TAF1 gene expression in X-linked Dystonia Parkinsonism [RNA-Seq]

| PRJNA1053321 | ENA

G-quadruplexes within the SVA retrotransposon modulate TAF1 gene expression in X-linked Dystonia Parkinsonism [ChIP-seq]

Project description:G-quadruplexes within the SVA retrotransposon modulate TAF1 gene expression in X-linked Dystonia Parkinsonism [ChIP-seq]

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Homo sapiens

Project description:X linked dystonia parkinsonism

| PRJNA93155 | ENA

X linked dystonia parkinsonism

Project description:Investigation of expression profile in XDP brains. Keywords: an XDP patient and neurologically normal control

2006-02-03 | GSE3064 | GEO

Genome and Transcriptome Analysis of X-Linked Dystonia Parkinsonism Cohort

Project description:<p>X-linked Dystonia-Parkinsonism (XDP) is a long-standing quandary in human disease genetics. XDP is predominantly observed on Panay island in the Philippines. This study is one of the first of its kind to interrogate an unsolved Mendelian disorder by integrating genome and transcriptome assembly methods using Illumina, 10X Genomics, Pacific Biosciences, and Agilent genome targeting technologies. These data provide strong evidence for a pathogenic link between a noncoding SVA retrotransposon and XDP. We demonstrate that this Mendelian disorder is associated with a sine-VNTR-Alu (SVA) retrotransposon that inserted into the TAF1 gene and is shared by all XDP probands, yet never observed in controls from worldwide populations. Transcriptome assembly in iPSC-derived neural stem cells (NSCs) and neurons revealed that this SVA caused aberrant splicing and significant intron retention, which was negatively correlated with TAF1 expression. Remarkably, CRISPR/Cas9 excision of the SVA rescued the aberrant transcriptional signature and normalized expression of TAF1 in patient-derived NSCs.</p>

| phs001525 | dbGaP

Proteomic Analysis of X-Linked Dystonia Parkinsonism Disease Medium Spiny Neurons from Patient-Induced Pluripotent Stem Cells

Project description:X-linked dystonia-parkinsonism (XDP) is a rare neurodegenerative disease endemic to the Philippines. The genetic cause for XDP is an insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within intron 32 of TATA-binding protein associated factor 1 (TAF1) that causes an alteration of TAF1 splicing, partial intron retention, and decreased transcription. Although TAF1 is expressed in all organs, medium spiny neurons (MSNs) within the striatum are one of the cell types most affected in XDP. To define how mutations in the TAF1 gene lead to MSN vulnerability, we carried out a proteomic analysis of human XDP patient-derived neural stem cells (NSCs) and MSNs derived from induced pluripotent stem cells. NSCs and MSNs were grown in parallel and subjected to quantitative proteomic analysis in data-independent acquisition mode on the Orbitrap Eclipse Tribrid mass spectrometer. Subsequent functional enrichment analysis demonstrated that neurodegenerative disease-related pathways, such as Huntington s disease, spinocerebellar ataxia, cellular senescence, mitochondrial function and RNA binding metabolism, were highly represented. We used weighted coexpression network analysis (WGCNA) of the NSC and MSN proteomic data set to uncover disease-driving network modules. Three of the modules significantly correlated with XDP genotype when compared to the non-affected control and were enriched for DNA helicase and nuclear chromatin assembly, mitochondrial disassembly, RNA location and mRNA processing. Consistent with aberrant mRNA processing, we found splicing and intron retention of TAF1 intron 32 in XDP MSN. We also identified TAF1 as one of the top enriched transcription factors, along with YY1, ATF2, USF1 and MYC. Notably, YY1 has been implicated in genetic forms of dystonia. Overall, our proteomic data set constitutes a valuable resource to understand mechanisms relevant to TAF1 dysregulation and to identify new therapeutic targets for XDP.

2023-07-05 | MSV000092344 | MassIVE

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