Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

TDP-43 binds to RNA G-quadruplex structure and regulates mRNA stability and translation

ABSTRACT: TDP-43 is a hallmark protein associated with neurodegenerative diseases. Recent studies revealed TDP-43 as an RNA G-quadruplex (rG4) binding protein, impacting mRNA transport and function. However, our understanding on the interaction between TDP-43 and RNA secondary structure remains poorly understood. Additionally, reports on specific rG4 targets regulated by TDP-43 are limited. Herein, we show that TDP-43 exhibits a preference for binding to the rG4 structure under K+ condition by a high-throughput RNA Bind-n-Seq method. Besides, we find that loss of TDP-43 contributes to a decrease in mRNA structure in the transcriptome by using the newly developed SHALiPE-seq technology. By analyzing the SHALiPE-seq data of TDP-43 binding sites, we further demonstrate that the reduction in structural complexity is likely due to the loss of TDP-43 binding to the RNA targets, especially in the 3'UTR. Importantly, our transcript-specific investigation reveals that TDP-43 binds to a novel rG4 structure in the 3'UTR of SLC1A5 mRNA, promoting the mRNA stability and translation. Our findings not only offer new insights into the role of TDP-43 in regulating RNA structure such as rG4, but also contribute to a better understanding of its broader functions and provide potential targets for therapeutic strategies in TDP43-related diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272797 | GEO | 2025/09/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

TDP-43 binds to RNA G-quadruplex structure and regulates mRNA stability and translation [RBNS]

Project description:TDP-43 is a hallmark protein associated with neurodegenerative diseases. Recent studies revealed TDP-43 as an RNA G-quadruplex (rG4) binding protein, impacting mRNA transport and function. However, our understanding on the interaction between TDP-43 and RNA secondary structure remains poorly understood. Additionally, reports on specific rG4 targets regulated by TDP-43 are limited. Herein, we show that TDP-43 exhibits a preference for binding to the rG4 structure under K+ condition by a high-throughput RNA Bind-n-Seq method. Besides, we find that loss of TDP-43 contributes to a decrease in mRNA structure in the transcriptome by using the newly developed SHALiPE-seq technology. By analyzing the SHALiPE-seq data of TDP-43 binding sites, we further demonstrate that the reduction in structural complexity is likely due to the loss of TDP-43 binding to the RNA targets, especially in the 3'UTR. Importantly, our transcript-specific investigation reveals that TDP-43 binds to a novel rG4 structure in the 3'UTR of SLC1A5 mRNA, promoting the mRNA stability and translation. Our findings not only offer new insights into the role of TDP-43 in regulating RNA structure such as rG4, but also contribute to a better understanding of its broader functions and provide potential targets for therapeutic strategies in TDP43-related diseases.

2025-09-01 | GSE273602 | GEO

RNA sequencing of mice expressing NLS-hTDP-43

Project description:TAR DNA-binding protein 43 (TDP-43) is normally a nuclear RNA-binding protein that exhibits a range of functions including regulation of alternative splicing, RNA trafficking and RNA stability. However, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved, and is mislocalized to the cytoplasm where it forms distinctive aggregates. We previously developed a mouse model expressing human TDP-43 with a mutation in its nuclear localization signal (ΔNLS-hTDP-43) so that the protein preferentially localizes to the cytoplasm. These mice did not exhibit a significant number of cytoplasmic aggregates, but did display a loss of endogenous mouse nuclear TDP-43 as well as dramatic changes in gene expression as measured by microarray. Here, we analyze RNA-sequencing data from the ∆NLS-hTDP-43 mouse model, together with published RNA-sequencing data obtained previously from TDP-43 antisense oligonucleotide (ASO) knockdown mice and High Throughput Sequencing of RNA isolated by CrossLinking ImmunoPrecipitation (HITS-CLIP) data of TDP-43’s RNA binding targets to further investigate the dysregulation of gene expression in the ∆NLS model. This analysis reveals that the transcriptomic effects of the overexpression of the ΔNLS-hTDP-43 transgene are likely due to a gain of cytoplasmic function. Moreover, cytoplasmic TDP-43 expression alters transcripts that regulate chromatin assembly, the nucleolus, lysosomal function, and histone 3’ untranslated region (UTR) processing. These transcriptomic alterations correlate with observed histologic abnormalities in heterochromatin structure and nuclear size in transgenic mouse and human brains.

2015-10-15 | GSE65973 | GEO

Knockdown of transactive response DNA-binding protein TDP-43 downregulates histone deacetylase 6

Project description:TDP-43 is an RNA/DNA-binding protein implicated in transcriptional repression and mRNA processing. Inclusions of TDP-43 are hallmarks of frontotemporal dementias and amyotrophic lateral sclerosis. Besides aggregation of TDP-43, loss of nuclear localization is observed in disease. To identify relevant targets of TDP-43, we performed an expression profiling study. Thereby, histone deacetylase 6 (HDAC6) downregulation was discovered upon TDP-43 silencing on mRNA and protein level in human embryonic kidney HEK293E and neuronal SH-SY5Y cells. This was accompanied by accumulation of the major HDAC6 substrate, acetyl-tubulin. Expression of wild-type but neither RNA-binding- nor nuclear-localization-deficient TDP-43 restored HDAC6 expression. Moreover, TDP-43 bound specifically to HDAC6 mRNA arguing for a direct functional interaction. Importantly, in vivo validation in TDP-43 knockout Drosophila melanogaster also showed HDAC6 mRNA decrease. HDAC6 is necessary for protein aggregate formation and degradation. Indeed, downregulation of HDAC6 reduced aggregate formation and increased cytotoxicity of expanded poly-glutamine ataxin-3 in TDP-43 silenced cells. This was completely restored by co-transfection with HDAC6. In conclusion, loss of functional TDP-43 causes HDAC6 downregulation and might thereby contribute to pathogenesis.

2009-10-20 | GSE18632 | GEO

Identification of Neuronal RNA Targets of TDP-43-Containing Ribonucleoprotein Complexes

2010-11-04 | GSE25032 | GEO

Functional TDP-43 amyloids bind sarcomeric mRNA to direct skeletal muscle formation

Project description:Cytoplasmic aggregates of TDP-43 are found in neuronal and skeletal muscle diseases yet it is not understood how these protein aggregates relate to the biological function of TDP-43. By examining normal skeletal muscle formation, we discovered TDP-43 redistributes from the nucleus into the cytoplasm and forms higher-ordered aggregates. These skeletal muscle TDP-43 aggregates adopt an amyloid-like structure capable of binding RNA. In skeletal muscle, TDP-43 binds UG-rich, sarcomeric mRNAs and oligomerizes on these long mRNA transcripts facilitating amyloid formation. Tissue specific genetic deletion of TDP-43 in skeletal muscle disrupts the formation and maintenance of the sarcomere and mislocalizes sarcomeric mRNAs. Thus, cytoplasmic, amyloid-like TDP-43 aggregates that traffic mRNAs could serve as a precursor to pathological TDP-43 aggregates common in degenerative neuromuscular disease.

2018-09-05 | GSE104796 | GEO

Identification of Neuronal RNA Targets of TDP-43-Containing Ribonucleoprotein Complexes

Project description:We identify the RNA targets of TAR DNA-binding protein 43 (TDP-43) from cortical neurons by RNA immunoprecipitation followed by deep sequencing (RIP-seq). We identify 4352 highly enriched RNA targets of TDP-43. We determined that the canonical TDP-43 binding site (TG)n was 55.1-fold enriched in our TDP-43 library. Moreover, our analysis shows there is often an adenine in the middle of the motif, (TG)nTA(TG)m. TDP-43 RNA targets are particularly enriched for Gene Ontology terms related to RNA metabolism, neuronal development, and synaptic function. Examination of TDP-43 RNA targets in rat cortical neurons by RIP-seq. Chantelle F. Sephton isolated the TDP-43:RNA complexes and generated the cDNA library for deep sequencing. Email: chantelle.sephton@utsouthwestern.edu Phone: 214-648-4119 Fax: 214-648-1801 ULR: http://www8.utsouthwestern.edu/utsw/cda/dept120915/files/151135.html Organization name: University of Texas Southwestern Medical Center at Dallas Department: Neuroscience Lab: Gang Yu lab Street: 6000 Harry Hines Blvd. City: Dallas State: Texas ZIP: 75390 Country: USA

2010-11-04 | E-GEOD-25032 | biostudies-arrayexpress

TDP-43 iCLIP of SHSY5Y cells

Project description:TDP-43 is an important RNA binding protein. To better understand its binding targets in human neurons, we performed TDP-43 iCLIP on SHSY5Y cells.

2022-02-02 | E-MTAB-11243 | biostudies-arrayexpress

Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons [RNA-Seq]

Project description:Loss of the nuclear RNA binding protein TAR DNA binding protein-43 (TDP-43) into cytoplasmic aggregates is the strongest correlate to neurodegeneration in amyotrophic lateral sclerosis and frontotemporal degeneration. The molecular changes associated with the loss of nuclear TDP-43 in human tissues are not entirely known. Using a novel subcellular fractionation and fluorescent activated cell sorting method to enrich for diseased neuronal nuclei without TDP-43 from post-mortem FTD-ALS human brain, we characterized the effects of TDP-43 loss on the transcriptome and chromatin accessibility. Nuclear TDP-43 loss is associated with gene expression changes that affect RNA processing, nucleocytoplasmic transport, histone processing and DNA damage. Loss of nuclear TDP-43 was also associated with chromatin decondensation around long interspersed nuclear elements (LINEs) and increased LINE1 DNA content. Moreover, loss of TDP-43 leads to increased retrotransposition that can be inhibited with antiretroviral drugs, suggesting that TDP-43 neuropathology is associated with altered chromatin structure including decondensation of LINEs.

2019-03-15 | GSE126542 | GEO

Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons [ATAC-Seq]

2019-03-15 | GSE126541 | GEO

MiR-129-5p downregulates HuD expression impairing neuritogenesis in Amyotrophic Lateral Sclerosis

Project description:Amyotrophic lateral sclerosis (ALS) involves the degeneration of brain and spinal cord motor neurons. Mutations in Superoxide Dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43) and Fused-in-Sarcoma (FUS) account for 20-30 % of the familial ALS (fALS) cases. The RNA-binding proteins TDP-43 and FUS function in mRNA and miRNA biogenesis. MiRNAs are required for survival of neurons and deregulation of miRNA expression has been reported in several neurodegenerative disorders. Here, we report the dysregulation of DROSHA, DGCR8, and DICER in human neuroblastoma SH-SY5Y cells expressing the ALS-associated SOD1(G93A) mutant protein. MiRNA profiling in SH-SY5Y/SOD1(G93A) cells and transgenic SOD1(G93A) mice revealed upregulation of miR-129-5p at the early stage of disease. Moreover, miR-129-5p is also upregulated in lymphocytes of sporadic ALS patients. We demonstrate that miR-129-5p targets ELAVL4/HuD mRNA by binding to its 3’ UTR, which reduces HuD expression and impairs differentiation and neurite outgrowth. Conversely, treatment with an antagomir or complementation with HuD protein restores neuritogenesis. Collectively, our study identifies miR-129-5p and HuD as key regulators of neuronal differentiation and as potential therapeutic targets for ALS.

2018-02-01 | GSE94379 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data