Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA282692 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2002765_1.fastq.gz | Fastqsanger.gz | |||
| SRR2002765_2.fastq.gz | Fastqsanger.gz | |||
| SRR2002766_1.fastq.gz | Fastqsanger.gz | |||
| SRR2002766_2.fastq.gz | Fastqsanger.gz |
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Project description:MicroRNAs (miRNAs) play important roles in a wide range of cellular processes. Aberrant regulation of miRNA genes contributes to human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs whose expression levels are regulated by TDP-43 using RNA-Seq coupled with siRNA-mediated knockdown approach. TDP-43 knocking down affected the expression of a number of miRNAs. Alterations in isomiR patterns and miRNA arm selection after TDP-43 knockdown suggest a role of TDP-43 in miRNA editing. We examined correlation of selected TDP-43 associated miRNAs and their candidate target genes in human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p expression. On the other hand, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Low expression of miR-500a-3p was associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Our experiments reveal that cancer-associated genes LIF and PAPPA may be targets of miR-500a-3p. Together with other studies, our work suggests that TDP-43-regulated miRNAs may play multi-facet roles in the pathogenesis of cancer. small RNA seq in SH-SY-5Y, SNB-19 and HT22 (TDP-43 siRNA VS Control siRNA)
2016-08-02 | E-GEOD-85065 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) play important roles in a wide range of cellular processes. Aberrant regulation of miRNA genes contributes to human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs whose expression levels are regulated by TDP-43 using RNA-Seq coupled with siRNA-mediated knockdown approach. TDP-43 knocking down affected the expression of a number of miRNAs. Alterations in isomiR patterns and miRNA arm selection after TDP-43 knockdown suggest a role of TDP-43 in miRNA editing. We examined correlation of selected TDP-43 associated miRNAs and their candidate target genes in human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p expression. On the other hand, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Low expression of miR-500a-3p was associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Our experiments reveal that cancer-associated genes LIF and PAPPA may be targets of miR-500a-3p. Together with other studies, our work suggests that TDP-43-regulated miRNAs may play multi-facet roles in the pathogenesis of cancer.
2016-08-02 | GSE85065 | GEO
Project description:TAR DNA-binding protein 43 (TDP-43) is the major protein component of neuronal inclusions characterizing the adult-onset neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). Whereas TDP-43 was originally identified as a DNA-binding protein that bound the HIV-1 trans-activation response (TAR) DNA element, recent work elucidating its role in neurodegenerative disease pathogenesis has largely focused on TDP-43’s role as an RNA-binding protein. Here, we demonstrate that in human cells, TDP-43 binds DNA genome-wide, with strong enrichment at small nuclear RNA (snRNA) genes. Moreover, TDP-43 binding to snRNA genes is not dependent on RNA, and the snRNA products of TDP-43-bound sites are incorporated into Smith antigen-containing snRNPs. Furthermore, TDP-43 knockdown increases expression of bound snRNA genes, supporting a role for TDP-43 in the negative regulation of snRNA biogenesis. Finally, ALS-associated missense mutations in the gene encoding TDP-43, TARDBP, reduce binding to snRNA genes. Together, our data suggest that the DNA-binding role of TDP-43 is important in health and in disease, and aberrant TDP-43 binding to snRNA gene loci may alter splicing function in ALS and FTLD-TDP.
2023-12-21 | GSE117873 | GEO
Project description:C. elegans mutants deleted for TDP-1, an ortholog of the neurodegeneration-associated RNA binding protein TDP-43, display only mild phenotypes. Nevertheless, transcriptome sequencing revealed that many RNAs were altered in accumulation and/or processing in the mutant. Analysis of these transcriptional abnormalities demonstrates that a primary function of TDP-1 is to limit formation or stability of double-stranded RNA. Specifically, we found that deletion of tdp-1: 1) preferentially alters the accumulation of RNAs with inherent double stranded structure (dsRNA); 2) increases the accumulation of nuclear dsRNA foci, 3) enhances the frequency of adenosine-to-inosine RNA editing, and 4) dramatically increases the amount of transcripts immunoprecipitable with a dsRNA-specific antibody, including intronic sequences, RNAs with antisense overlap to another transcript, and transposons. We also show that TDP-43 knockdown in human cells results in accumulation of dsRNA , indicating that suppression of dsRNA is a conserved function of TDP-43 in mammals. Altered accumulation of structured RNA may account for some of the previously described molecular phenotypes (e.g., altered splicing) resulting from reduction of TDP-43 function. 24 samples: 3 tdp-1 polyA samples with 3 N2 controls, 3 tdp1J2 immunoprecipitated samples and tdp1 total RNA input with 3 N2 J2 immunoprecipitated controls (with N2 input), 3 tdp1 total RNA samples for RNA editing analysis with 3 N2 total RNA controls and an adr-2 mutant control, 2 tdp1 CHIPseq samples with RNAsecontrol.
2014-11-19 | E-GEOD-61581 | biostudies-arrayexpress
Project description:UNC13A contains a novel cryptic exon which is expressed upon TDP-43 knockdown. However, it also features TDP-43 regulated intron retention of a downstream intron. To investigate the correlation of these two events, we performed Nanopore sequencing of amplicons from SHSY5Y cells with inducible TDP-43 knockdown, and FTD patient RNA samples
2022-02-10 | E-MTAB-11244 | biostudies-arrayexpress
Project description:TAR DNA-binding protein 43 (TDP-43) is an RNA/DNA-binding protein involved in many aspects of RNA metabolism, but its molecular roles in regulating gene and tTransposable eElements (TEs) transcription transcription is not extensively explored. TDP-43 loss-of-function via due to progressive cytoplasmic aggregations serves as a pathological hallmark and potential causality for several neurodegenerative diseases. While rRecent evidence suggest TDP-43 acute knockdown of TDP-43 affects the formation of R-loops formation, a nuclear DNA:RNA hybrid structures implicated in transcription regulation, . However, how its stable and chronic functional perturbation of TDP-43, which more closely resembles age-related neurodegeneration, impact global transcriptome via R-loop dysregulation remains unclear. Here we show demonstrate that stable and prolonged TDP-43 loss-of-function results in slowed impaired cell proliferation and impaired DNA damage response. At the molecular level, TDP-43 stable knockdown impacts key gene expression through concomitantly altering intragenic R-loops dynamics and its crosstalk with and thea DNA covalent modification 5-hydroxymethylcytosine (5hmC) in cis, as well as long- range R-loops-mediated enhancer-promoter interactions in trans. Furthermore, we find TDP-43 stable knockdown induces massive disease-related TEstransposable elements (TEs) activation via influencing R-loop and 5hmC homeostasis in many of these loci. Our results highlight previous underdeveloped transcriptional roles of TDP-43 via R-loops regulation in coding genes, distal regulatory elements and TEs, and suggest that TDP-43 proteinopathies transcriptionally contributes to the etiology of neurodegenerative disorders.
2024-01-03 | GSE230407 | GEO
Project description:TAR DNA-binding protein 43 (TDP-43) is an RNA/DNA-binding protein involved in many aspects of RNA metabolism, but its molecular roles in regulating gene and tTransposable eElements (TEs) transcription transcription is not extensively explored. TDP-43 loss-of-function via due to progressive cytoplasmic aggregations serves as a pathological hallmark and potential causality for several neurodegenerative diseases. While rRecent evidence suggest TDP-43 acute knockdown of TDP-43 affects the formation of R-loops formation, a nuclear DNA:RNA hybrid structures implicated in transcription regulation, . However, how its stable and chronic functional perturbation of TDP-43, which more closely resembles age-related neurodegeneration, impact global transcriptome via R-loop dysregulation remains unclear. Here we show demonstrate that stable and prolonged TDP-43 loss-of-function results in slowed impaired cell proliferation and impaired DNA damage response. At the molecular level, TDP-43 stable knockdown impacts key gene expression through concomitantly altering intragenic R-loops dynamics and its crosstalk with and thea DNA covalent modification 5-hydroxymethylcytosine (5hmC) in cis, as well as long- range R-loops-mediated enhancer-promoter interactions in trans. Furthermore, we find TDP-43 stable knockdown induces massive disease-related TEstransposable elements (TEs) activation via influencing R-loop and 5hmC homeostasis in many of these loci. Our results highlight previous underdeveloped transcriptional roles of TDP-43 via R-loops regulation in coding genes, distal regulatory elements and TEs, and suggest that TDP-43 proteinopathies transcriptionally contributes to the etiology of neurodegenerative disorders.
2024-01-03 | GSE230406 | GEO
Project description:Purpose: The goal of this stuydy was to apply transcriptome profiling (RNA-seq) to human cells that either express or which lack the TDP-43 protein. Methods: mRNA profiles of TDP-43 KO HeLa cells and "rescued" TDP-43 KO cells wherein a wildtype TDP-43 transgene was re-expressed at endogenous levels were generated by deep sequencing, in triplicate, on Illumina’s HiSeq 2500 using 2x70bp paired-end reads, generating 104.4-128.2 million reads (52.2-64.1 million pairs) per sample. . The sequence reads that passed quality filters were analyzed at the transcript isoform level with TopHat2 followed by Cufflinks Cuffmerge and Cuffdiff to define transcripts and establish their abundance and finally to perform differential gene expression analysis, using the assembled known plus novel transcripts . Results: Using an optimized data analysis workflow, we mapped approximately 50-60 million reads per sample to the human genome (build hg19) and identified transcripts whose abundance differed between the TDP-43 KO versus "rescued" conditions. Conclusions: Our study presents a detailed analysis of the impact of the knockout of TDP-43 on the transcriptome of a human cell line. The results reported here should provide a framework for defining transcripts whose abundnace and splicing are regulated by TDP-43.
2019-09-09 | GSE136366 | GEO
Project description:Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43 knockdown neurons and decreased 2-transferrin levels in patient CSF. Whole proteome quantification identified upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons. Luciferase report assays and chromatin immunoprecipitation suggest that TDP-43 represses VPS4B transcription. Preventing VPS4B upregulation or expression of its functional antagonist ALIX restores trafficking of recycling endosomes. Proteomic analysis revealed broad reduction in surface expression of key receptors upon TDP-43 knockdown including ErbB4, the neuregulin 1 receptor. TDP-43 knockdown delays surface delivery of ErbB4. ErbB4 overexpression, but not neuregulin 1 stimulation, prevents dendrite loss upon TDP-43 knockdown. Thus, impaired recycling of ErbB4 and other receptors to the cell surface may contribute to TDP-43 induced neurodegeneration by blocking trophic signaling.
2016-09-29 | PXD004744 | Pride
Project description:TDP-43-coding mutations are found among ALS patients. In oder to express human mutant TDP-43 protein in the mouse under the control of the endogenous Tardp promoter, we have generate a mouse line wit 300% elevated TDP-43 level.
2014-05-21 | GSE39585 | GEO