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TDP-1, the C. elegans ortholog of TDP-43, limits the accumulation of double stranded RNA

ABSTRACT: 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.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE61581 | GEO | 2014/11/19

SECONDARY ACCESSION(S): PRJNA261532

REPOSITORIES: GEO

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TDP-1, the C. elegans ortholog of TDP-43, limits the accumulation of double stranded RNA

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

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TDP-43 prevents endogenous RNAs from triggering a lethal RIG-I-dependent interferon response

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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

ALS implicated protein TDP-43 sustains levels of STMN2 a mediator of motor neuron growth and repair

Project description:The discovery that TDP-43 mutations cause familial ALS and that many patients display pathological TDP-43 mislocalization has nominated altered RNA metabolism as a potential disease mechanism. Despite its importance, the identity of RNAs regulated by TDP-43 in motor neurons remains poorly understood. Here, we report transcripts whose abundances in human motor neurons are sensitive to TDP-43 depletion. Notably, we found STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown, in patient-specific motor neurons, following TDP-43 mislocalization, and in the postmortem patient spinal cords. Loss of STMN2 upon reduced TDP-43 function was due to the emergence of a cryptic exon, which is of substantial functional importance, as we further demonstrate that STMN2 is necessary for both axonal outgrowth and repair. Importantly, post-translational stabilization of STMN2 could rescue neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. We propose restoring STMN2 expression warrants future examination as an ALS therapeutic strategy.

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TDP-43 regulates cancer-associated microRNAs

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The C. elegans ortholog of TDP-43 regulates the chromatin localization of the heterochromatin protein 1 homolog, HPL-2

Project description:TDP-1 is the C. elegans ortholog of mammalian TDP-43, which is strongly implicated in the etiology of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). We discovered that deletion of the tdp-1 gene results in enhanced transcriptional gene silencing leading to increased sensitivity to heritable RNA interference (RNAi). As heritable RNAi in C. elegans depends on chromatin changes moderated by HPL-2, a homolog of heterochromatin protein 1 (HP1), we investigated the interaction of TDP-1 and HPL-2. We find that TDP-1 and HPL-2 interact directly, and loss of TDP-1 dramatically alters the chromatin association of HPL-2. We have shown previously that deletion of the tdp-1 gene results in transcriptional alterations and the accumulation of double-stranded (ds) RNA. These molecular changes are replicated in an hpl-2 deletion strain, consistent with HPL-2 acting downstream of TDP-1 to modulate these aspects of RNA metabolism. Our observations identify novel mechanisms by which HP1 homologs can be recruited to chromatin, and by which nuclear depletion of human TDP-43 could lead to disease-relevant changes in RNA metabolism.

2018-05-17 | GSE100829 | GEO

Major hnRNP proteins act as general TDP-43 functional modifiers both in Drosophila and human neuronal cells.

Project description:Nuclear factor TDP-43 is known to play an important role in several neurodegenerative pathologies. In general, TDP-43 is an abundant protein within the eukaryotic nucleus that binds to many coding and non-coding RNAs and influence their processing. Using Drosophila, we have performed a functional screening to establish the ability of major hnRNP proteins to affect TDP-43 overexpression/depletion phenotypes. Interestingly, we observed that lowering hnRNP and TDP-43 expression has a generally harmful effect on flies locomotor abilities. In parallel, our study has also identified a distinct set of hnRNPs that is capable of powerfully rescuing TDP-43 toxicity in the fly eye (Hrb27c, CG42458, Glo and Syp). Most importantly, removing the human orthologs of Hrb27c (DAZAP1) in human neuronal cell lines can correct several pre-mRNA splicing events altered by TDP-43 depletion. Moreover, using RNA sequencing analysis we show that DAZAP1 and TDP-43 can co-regulate an extensive number of cellular pathways potentially important for the neuron biology. Our results suggest that changes in hnRNP expression levels can significantly modulate TDP-43 functions and affect pathological outcomes.

2017-05-31 | GSE97262 | GEO

TDP-43 is a genome-wide DNA-binding protein and regulator of snRNA expression

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.

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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

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