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Publication

An Integrative Study of Protein-RNA Condensates Identifies Scaffolding RNAs and Reveals Players in Fragile X-Associated Tremor/Ataxia Syndrome.

Cell reports | 2018

Recent evidence indicates that specific RNAs promote the formation of ribonucleoprotein condensates by acting as scaffolds for RNA-binding proteins (RBPs). We systematically investigated RNA-RBP interaction networks to understand ribonucleoprotein assembly. We found that highly contacted RNAs are structured, have long UTRs, and contain nucleotide repeat expansions. Among the RNAs with such properties, we identified the FMR1 3' UTR that harbors CGG expansions implicated in fragile X-associated tremor/ataxia syndrome (FXTAS). We studied FMR1 binding partners in silico and in vitro and prioritized the splicing regulator TRA2A for further characterization. In a FXTAS cellular model, we validated the TRA2A-FMR1 interaction and investigated implications of its sequestration at both transcriptomic and post-transcriptomic levels. We found that TRA2A co-aggregates with FMR1 in a FXTAS mouse model and in post-mortem human samples. Our integrative study identifies key components of ribonucleoprotein aggregates, providing links to neurodegenerative disease and allowing the discovery of therapeutic targets.

Pubmed ID: 30566867 RIS Download

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Additional research tools detected in this publication

Antibodies used in this publication

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This is a list of tools and resources that we have found mentioned in this publication.

R Project for Statistical Computing (tool)

RRID:SCR_001905

Software environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.

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QIAGEN (tool)

RRID:SCR_008539

A commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.

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RMA Express (tool)

RRID:SCR_008549

RMAExpress is a standalone GUI program for Windows (and Linux) to compute gene expression summary values for Affymetrix Genechip data using the Robust Multichip Average expression summary and to carry out quality assessment using probe-level metrics. It does not require R nor is it dependent on any component of the BioConductor project. If focuses on processing 3'' IVT expression arrays, exon and WT gene arrays. What is RMA? RMA is the Robust Multichip Average. It consists of three steps: a background adjustment, quantile normalization (see the Bolstad et al reference) and finally summarization. Some references (currently published) for the RMA methodology are: Bolstad, B.M., Irizarry R. A., Astrand, M., and Speed, T.P. (2003), A Comparison of Normalization Methods for High Density Oligonucleotide Array Data Based on Bias and Variance. Bioinformatics 19(2):185-193 Supplemental information Rafael. A. Irizarry, Benjamin M. Bolstad, Francois Collin, Leslie M. Cope, Bridget Hobbs and Terence P. Speed (2003), Summaries of Affymetrix GeneChip probe level data Nucleic Acids Research 31(4):e15 Irizarry, RA, Hobbs, B, Collin, F, Beazer-Barclay, YD, Antonellis, KJ, Scherf, U, Speed, TP (2002) Exploration, Normalization, and Summaries of High Density Oligonucleotide Array Probe Level Data. Accepted for publication in Biostatistics. [Abstract, PDF, PS, Complementary Color Figures-PDF, Software] What do I need? You will need the appropriate CDF and CEL files for your dataset. For Exon and WT Gene arrays, the PGF and CLF should be used instead of the CDF file to build a CDFRME file. The process for doing this is explained in the user manual. Some pre-built CDFRME files are also available. CDFRME files HuEx_CDFRME.zip (95.9MB) HuGene_CDFRME.zip (5.5MB) MoEx_CDFRME.zip (79.6MB) MoGene_CDFRME.zip (6.3MB) RaEx_CDFRME.zip (48.4MB) RaGene_CDFRME.zip (5.7MB) Can I use affy/BioConductor instead? Of course. Hypothetically you will get the same results from both places, provided you have consistent settings in affy/BioConductor and RMAExpress. Some people prefer the power and flexibility of R and others like the point and click simplicity of a GUI. RMAExpress caters to the second option. Since RMAExpress outputs the computed expression values to a text file, you may of course load the expression measures into R and use features of Bioconductor for the analysis of your gene expression values. You can of course open the results file in any other application that supports importing plain text files. Will I get the same results as I would using affy/Bioconductor? Yes. The results from RMAExpress should be consistent. What are the machine requirements? A good rule of thumb is the more RAM you have the better. I would recommend at least 1GB, though 512MB will work in most situations. At this point the program has been tested using Windows 2000, Windows XP, Windows Vista and Linux. Most recently I have had a report of over 10,000 arrays processed in a single session. Can I do any quality assessment? Yes, store the residuals when you compute the expression values. Then you may examine chip pseudo-images of the residuals. Note that high positive residuals are colored increasingly read and low negative residuals are colored increasingly blue. To better interpret these images and gain a better feel for what is typical you may visit the PLM Image Gallery where images for a number of different datasets are shown. Access to the NUSE and RLE quality assessment metrics is also provided. How do I download and install it? Click here for the current release Windows version. Use the installer to install the program. The current release version number is 1.0 (released June 29, 2008). A pre-built linux version is not currently available, but you may build it using the source code. You can download pre-release versions from the following table (the release versions will be more stable, the development versions may have features that are incomplete or will be removed or altered before the next release was supported by the PGA U01 HL66583.

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Millipore (tool)

RRID:SCR_008983

An Antibody supplier

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DEXSeq (tool)

RRID:SCR_012823

Software package focused on finding differential exon usage using RNA-seq exon counts between samples with different experimental designs. It provides functions that allows the user to make the necessary statistical tests based on a model that uses the negative binomial distribution to estimate the variance between biological replicates and generalized linear models for testing. The package also provides functions for the visualization and exploration of the results.

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Abcam (tool)

RRID:SCR_012931

A commercial antibody supplier which supplies primary and secondary antibodies, biochemicals, proteins, peptides, lysates, immunoassays and other kits.

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Dako (tool)

RRID:SCR_013530

An Antibody supplier; Dako was purchased by Agilent in 2012 and several years later the websites began to reflect the Dako products as part of the Agilent catalog.

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STAR (tool)

RRID:SCR_015899

Software performing alignment of high-throughput RNA-seq data. Aligns RNA-seq reads to reference genome using uncompressed suffix arrays.

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BioPlex (tool)

RRID:SCR_016144

Database of cell lines with each expressing a tagged version of a protein from the ORFeome collection. The overarching project goal is to determine protein interactions for every member of the collection.

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