Homo sapiens
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DRR216644_1.fastq.gz | Fastqsanger.gz | |||
| DRR216644_2.fastq.gz | Fastqsanger.gz | |||
| DRR216645_1.fastq.gz | Fastqsanger.gz | |||
| DRR216645_2.fastq.gz | Fastqsanger.gz | |||
| DRR216646.fastq.gz | Fastqsanger.gz |
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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: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
Project description:The mismatch repair (MMR) family is a highly conserved group of proteins that function in correcting base-base and insertion-deletion mismatches generated during DNA replication. To systematically investigate the mismatch repair pathway, we conducted a proteomic analysis and identified MMR-associated protein complexes using a tandem-affinity purification coupled with mass spectrometry (TAP-MS) method. In total, we identified 262 high-confidence candidate interaction proteins (HCIPs).
2016-02-08 | PXD003014 | Pride
Project description:The mismatch repair (MMR) family is a highly conserved group of proteins that function in correcting base-base and insertion-deletion mismatches generated during DNA replication. To systematically investigate the mismatch repair pathway, we conducted a proteomic analysis and identified MMR-associated protein complexes using a tandem-affinity purification coupled with mass spectrometry (TAP-MS) method. In total, we identified 262 high-confidence candidate interaction proteins (HCIPs).
2016-03-13 | MSV000079578 | MassIVE
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
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
Project description:Using a TIP-seq protocol (specifically isolating transposon insertion junctions) we determined that the Ty1 retrotransposon targets tRNA genes and, in particular, we determined that the transposon inserts into nucleosomal DNA in an asymmetric pattern. TIP-seq recovery of transposon insertion junctions in haploid and diploid yeast
2012-01-01 | E-GEOD-33986 | biostudies-arrayexpress
Project description:Preferential Protection of Genes Sequence by DNA Mismatch Repair
| PRJNA386856 | ENA
Project description:The experiments are done with three libraries by introducing base-pair perturbations on Widom 601: (1) poly(dA:dT) tract library (2) mismatch library (3) insertion library. And additional two more libraries based on native yeast genomic sequences: (4) Park97 mismatch library (5) Park97 insertion library. And we measured the nucleosome positioining in the base-pair resolution for before and after sliding by Chd1 chromatin remodeler.
2022-05-12 | GSE198440 | GEO
Project description:Reprogramming of H3K9me3-dependent heterochromatin is required for early development. How H3K9me3 is involved in early human development is, however, largely unclear. Here, we resolve the temporal landscape of H3K9me3 during human preimplantation development and its regulation for diverse hominoid-specific retrotransposons. At the 8-cell stage, H3K9me3 reprogramming at hominoid-specific retrotransposons termed SINE-VNTR-Alu (SVA) facilitates interaction between certain promoters and SVA-derived enhancers, facilitating the zygotic genome activation. In trophectoderm, de novo H3K9me3 domains prohibit pluripotent transcription factors from binding on hominoid-specific retrotransposons-derived regulatory elements for inner cell mass (ICM)-specific genes. H3K9me3 re-establishment at SVA elements in ICM is associated with higher transcription of DNA damage repair genes, compared to naïve human pluripotent stem cells. Our data demonstrate that species-specific reorganization of H3K9me3-dependent heterochromatin at hominoid-specific retrotransposons plays important roles during early human development, shedding light on how the epigenetic regulatory network for early development has evolved in mammals.
2022-07-14 | GSE176016 | GEO