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Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain.

Claudia Scheckel | Elodie Drapeau | Maria A Frias | Christopher Y Park | John Fak | Ilana Zucker-Scharff | Yan Kou | Vahram Haroutunian | Avi Ma'ayan | Joseph D Buxbaum | Robert B Darnell
eLife | 2016

Neuronal ELAV-like (nELAVL) RNA binding proteins have been linked to numerous neurological disorders. We performed crosslinking-immunoprecipitation and RNAseq on human brain, and identified nELAVL binding sites on 8681 transcripts. Using knockout mice and RNAi in human neuroblastoma cells, we showed that nELAVL intronic and 3' UTR binding regulates human RNA splicing and abundance. We validated hundreds of nELAVL targets among which were important neuronal and disease-associated transcripts, including Alzheimer's disease (AD) transcripts. We therefore investigated RNA regulation in AD brain, and observed differential splicing of 150 transcripts, which in some cases correlated with differential nELAVL binding. Unexpectedly, the most significant change of nELAVL binding was evident on non-coding Y RNAs. nELAVL/Y RNA complexes were specifically remodeled in AD and after acute UV stress in neuroblastoma cells. We propose that the increased nELAVL/Y RNA association during stress may lead to nELAVL sequestration, redistribution of nELAVL target binding, and altered neuronal RNA splicing.

Pubmed ID: 26894958

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


UCSC Genome Browser (tool)

RRID:SCR_005780

Portal to interactively visualize genomic data. Provides reference sequences and working draft assemblies for collection of genomes and access to ENCODE and Neanderthal projects. Includes collection of vertebrate and model organism assemblies and annotations, along with suite of tools for viewing, analyzing and downloading data.

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Addgene (tool)

RRID:SCR_002037

Non-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.

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CERAD - Consortium to Establish a Registry for Alzheimer's Disease (tool)

RRID:SCR_003016

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on January 4, 2023.Consortium that developed brief, standardized and reliable procedures for the evaluation and diagnosis of patients with Alzheimer's disease (AD) and other dementias of the elderly. These procedures included data forms, flipbooks, guidebooks, brochures, instruction manuals and demonstration tapes, which are now available for purchase. The CERAD assessment material can be used for research purposes as well as for patient care. CERAD has developed several basic standardized instruments, each consisting of brief forms designed to gather data on normal persons as well as on cognitively impaired or behaviorally disturbed individuals. Such data permit the identification of dementia based on clinical, neuropsychological, behavioral or neuropathological criteria. Staff at participating CERAD sites were trained and certified to administer the assessment instruments and to evaluate the subjects enrolled in the study. Cases and controls were evaluated at entry and annually thereafter including (when possible) autopsy examination of the brain to track the natural progression of AD and to obtain neuropathological confirmation of the clinical diagnosis. The CERAD database has become a major resource for research in Alzheimer's disease. It contains longitudinal data for periods as long as seven years on the natural progression of the disorder as well as information on clinical and neuropsychological changes and neuropathological manifestations.

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Bioconductor (tool)

RRID:SCR_006442

Software repository for R packages related to analysis and comprehension of high throughput genomic data. Uses separate set of commands for installation of packages. Software project based on R programming language that provides tools for analysis and comprehension of high throughput genomic data.

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InnateDB (tool)

RRID:SCR_006714

Publicly available database of the genes, proteins, experimentally-verified interactions and signaling pathways involved in the innate immune response of humans, mice and bovines to microbial infection. The database captures coverage of the innate immunity interactome by integrating known interactions and pathways from major public databases together with manually-curated data into a centralized resource. The database can be mined as a knowledgebase or used with the integrated bioinformatics and visualization tools for the systems level analysis of the innate immune response. Although InnateDB curation focuses on innate immunity-relevant interactions and pathways, it also incorporates detailed annotation on the entire human, mouse and bovine interactomes by integrating data (178,000+ interactions & 3,900+ pathways) from several of the major public interaction and pathway databases. InnateDB also has integrated human, mouse and bovine orthology predictions generated using Ortholgue software. Ortholgue uses a phylogenetic distance-based method to identify possible paralogs in high-throughput orthology predictions. Integrated human and mouse conserved gene order and synteny information has also been determined to provide further support for orthology predictions. InnateDB Capabilities: * View statistics for manually-curated innate immunity relevant molecular interactions. New manually curated interactions are submitted weekly. * Search for genes and proteins of interest. * Search for experimentally-verified molecular interactions by gene/protein name, interaction type, cell type, etc. * Search genes/interactions belonging to 3,900 pathways. * Visualize interactions using an intuitive subcellular localization-based layout in Cerebral. * Upload your own list of genes along with associated gene expression data (from up to 10 experimental conditions) to interactively analyze this data in a molecular interaction network context. Once you have uploaded your data, you will be able to interactively visualize interaction networks with expression data overlaid; carry out Pathway, Gene Ontology and Transcription Factor Binding Site over-representation analyses; construct orthologous interaction networks in other species; and much more. * Access curated interaction data via a dedicated PSICQUIC webservice.

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IntAct (tool)

RRID:SCR_006944

Open source database system and analysis tools for molecular interaction data. All interactions are derived from literature curation or direct user submissions. Direct user submissions of molecular interaction data are encouraged, which may be deposited prior to publication in a peer-reviewed journal. The IntAct Database contains (Jun. 2014): * 447368 Interactions * 33021 experiments * 12698 publications * 82745 Interactors IntAct provides a two-tiered view of the interaction data. The search interface allows the user to iteratively develop complex queries, exploiting the detailed annotation with hierarchical controlled vocabularies. Results are provided at any stage in a simplified, tabular view. Specialized views then allows "zooming in" on the full annotation of interactions, interactors and their properties. IntAct source code and data are freely available.

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Biological General Repository for Interaction Datasets (BioGRID) (tool)

RRID:SCR_007393

Curated protein-protein and genetic interaction repository of raw protein and genetic interactions from major model organism species, with data compiled through comprehensive curation efforts.

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MINT (tool)

RRID:SCR_001523

A database that focuses on experimentally verified protein-protein interactions mined from the scientific literature by expert curators. The curated data can be analyzed in the context of the high throughput data and viewed graphically with the MINT Viewer. This collection of molecular interaction databases can be used to search for, analyze and graphically display molecular interaction networks and pathways from a wide variety of species. MINT is comprised of separate database components. HomoMINT, is an inferred human protein interatction database. Domino, is database of domain peptide interactions. VirusMINT explores the interactions of viral proteins with human proteins. The MINT connect viewer allows you to enter a list of proteins (e.g. proteins in a pathway) to retrieve, display and download a network with all the interactions connecting them.

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Enrichr (tool)

RRID:SCR_001575

A web-based gene list enrichment analysis tool that provides various types of visualization summaries of collective functions of gene lists. It includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results using the JavaScript library, Data Driven Documents (D3). The software can also be embedded into any tool that performs gene list analysis. System-wide profiling of genes and proteins in mammalian cells produce lists of differentially expressed genes / proteins that need to be further analyzed for their collective functions in order to extract new knowledge. Once unbiased lists of genes or proteins are generated from such experiments, these lists are used as input for computing enrichment with existing lists created from prior knowledge organized into gene-set libraries.

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VennDiagram (tool)

RRID:SCR_002414

Software providing a set of functions to generate high-resolution Venn and Euler plots. Includes handling for several special cases, including two-case scaling, and extensive customization of plot shape and structure.

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HOMER (tool)

RRID:SCR_010881

Software tools for Motif Discovery and next-gen sequencing analysis. Used for analyzing ChIP-Seq, GRO-Seq, RNA-Seq, DNase-Seq, Hi-C and numerous other types of functional genomics sequencing data sets. Collection of command line programs for unix style operating systems written in Perl and C++.

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edgeR (tool)

RRID:SCR_012802

Bioconductor software package for Empirical analysis of Digital Gene Expression data in R. Used for differential expression analysis of RNA-seq and digital gene expression data with biological replication.

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TopHat (tool)

RRID:SCR_013035

Software tool for fast and high throughput alignment of shotgun cDNA sequencing reads generated by transcriptomics technologies. Fast splice junction mapper for RNA-Seq reads. Aligns RNA-Seq reads to mammalian-sized genomes using ultra high-throughput short read aligner Bowtie, and then analyzes mapping results to identify splice junctions between exons.TopHat2 is accurate alignment of transcriptomes in presence of insertions, deletions and gene fusions.

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ggplot2 (tool)

RRID:SCR_014601

Open source software package for statistical programming language R to create plots based on grammar of graphics. Used for data visualization to break up graphs into semantic components such as scales and layers.

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GENCODE (tool)

RRID:SCR_014966

Human and mouse genome annotation project which aims to identify all gene features in the human genome using computational analysis, manual annotation, and experimental validation.

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HEK293T (tool)

RRID:CVCL_0063

Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)

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IMR-32 (tool)

RRID:CVCL_0346

Cell line IMR-32 is a Cancer cell line with a species of origin Homo sapiens

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