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Genome-Scale Transcriptional Regulatory Network Models of Psychiatric and Neurodegenerative Disorders.

Cell systems | 2019

Transcriptional regulatory changes in the developing and adult brain are prominent features of brain diseases, but the involvement of specific transcription factors (TFs) remains poorly understood. We integrated brain-specific DNase footprinting and TF-gene co-expression to reconstruct a transcriptional regulatory network (TRN) model for the human brain. We identified key regulator TFs whose predicted target genes were enriched for differentially expressed genes in the prefrontal cortex of individuals with psychiatric and neurodegenerative diseases. Many of these TFs were further implicated in the same diseases through disruption of their binding sites by disease-associated SNPs and associations of TF loci with disease risk. Using primary human neural stem cells, we validated network predictions that link the TF POU3F2 to schizophrenia and bipolar disorder via both cis- and trans-acting mechanisms. Our models of brain-specific TF binding sites and target genes provide a resource for network analysis of brain diseases.

Pubmed ID: 30772379 RIS Download

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ATCC (tool)

RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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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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Ensembl (tool)

RRID:SCR_002344

Collection of genome databases for vertebrates and other eukaryotic species with DNA and protein sequence search capabilities. Used to automatically annotate genome, integrate this annotation with other available biological data and make data publicly available via web. Ensembl tools include BLAST, BLAT, BioMart and the Variant Effect Predictor (VEP) for all supported species.

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Scalable Nucleotide Alignment Program (tool)

RRID:SCR_005501

A sequence aligner software program that is 10-100x faster and simultaneously more accurate than existing tools like BWA, Bowtie2 and SOAP2. It runs on commodity x86 processors, and supports a rich error model that lets it cheaply match reads with more differences from the reference than other tools. This gives SNAP up to 2x lower error rates than existing tools and lets it match larger mutations that they may miss. SNAP also natively reads BAM, FASTQ, or gzipped FASTQ, and natively writes SAM or BAM, with built-in sorting, duplicate marking, and BAM indexing.

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PeproTech (tool)

RRID:SCR_006802

An Antibody supplier

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Suite of Nucleotide Analysis Programs (tool)

RRID:SCR_009399

THIS RESOURCE IS NO LONGER IN SERVICE, documented May 10, 2017. A pilot effort that has developed a centralized, web-based biospecimen locator that presents biospecimens collected and stored at participating Arizona hospitals and biospecimen banks, which are available for acquisition and use by researchers. Researchers may use this site to browse, search and request biospecimens to use in qualified studies. The development of the ABL was guided by the Arizona Biospecimen Consortium (ABC), a consortium of hospitals and medical centers in the Phoenix area, and is now being piloted by this Consortium under the direction of ABRC. You may browse by type (cells, fluid, molecular, tissue) or disease. Common data elements decided by the ABC Standards Committee, based on data elements on the National Cancer Institute''s (NCI''s) Common Biorepository Model (CBM), are displayed. These describe the minimum set of data elements that the NCI determined were most important for a researcher to see about a biospecimen. The ABL currently does not display information on whether or not clinical data is available to accompany the biospecimens. However, a requester has the ability to solicit clinical data in the request. Once a request is approved, the biospecimen provider will contact the requester to discuss the request (and the requester''s questions) before finalizing the invoice and shipment. The ABL is available to the public to browse. In order to request biospecimens from the ABL, the researcher will be required to submit the requested required information. Upon submission of the information, shipment of the requested biospecimen(s) will be dependent on the scientific and institutional review approval. Account required. Registration is open to everyone., documented September 29, 2016. A workbench tool to make existing population genetic software more accessible and to facilitate the integration of new tools for analyzing patterns of DNA sequence variation, within a phylogenetic context. Collectively, SNAP tools can serve as a bridge between theoretical and applied population genetic analysis. The exploration of DNA sequence variation for making inferences on evolutionary processes in populations requires the coordinated implementation of a Suite of Nucleotide Analysis Programs (SNAP), each bound by specific assumptions and limitations.

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NIH Blueprint NHP Atlas (tool)

RRID:SCR_010559

Atlas of gene expression in the developing rhesus macaque brain. This atlas is a free online resource with a unique set of data and tools aimed to create a developmental neuroanatomical framework for exploring the cellular and molecular architecture of the developing postnatal primate brain with direct relevance for human brain development. The atlas includes: * Microarray ** Microdissection: Fine structure transcriptional profiling across postnatal development for fine nuclear subdivisions of the prefrontal cortex, primary visual cortex, hippocampus, amygdala and ventral striatum ** Macrodissection: Gross structure transcriptional profiling across postnatal development for the same structures * ISH: ** Cellular resolution in situ hybridization image data of five major brain regions during postnatal developmental periods for genes clinically important for a variety of human neurodevelopmental disorders, including prefrontal cortex, primary visual cortex, hippocampus, amygdala and ventral striatum. ** Serial analysis of selected genes across the entire adult brain, focusing on cellular marker genes, genes with cortical area specificity and gene families important to neural function. * ISH Anatomic Search: Detailed gene expression search on the ISH data based on expert annotation * Reference Data: Developmental stage-specific reference series, consisting of magnetic resonance imaging (MRI) and Nissl histology to provide a neuroanatomical context for the gene expression data. These data and tools are designed to provide a valuable public resource for researchers and educators to explore neurodevelopment in non-human primates, and a key evolutionary link between other Web-based gene expression atlases for adult and developing mouse and human brain.

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F-Seq (tool)

RRID:SCR_010880

A software package that generates a continuous tag sequence density estimation allowing identification of biologically meaningful sites whose output can be displayed directly in the UCSC Genome Browser.

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LIMMA (tool)

RRID:SCR_010943

Software package for the analysis of gene expression microarray data, especially the use of linear models for analyzing designed experiments and the assessment of differential expression.

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ComBat (tool)

RRID:SCR_010974

Adjusting batch effects in microarray expression data using Empirical Bayes methods.

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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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Encode (tool)

RRID:SCR_015482

Consortium to build comprehensive parts list of functional elements in human genome. This includes elements that act at protein and RNA levels, and regulatory elements that control cells and circumstances in which gene is active. Data from 2012-present.

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Allen Human Brain Atlas: BrainSpan (Atlas of the Developing Brain) (tool)

RRID:SCR_008083

Atlas of developing human brain for studying transcriptional mechanisms involved in human brain development. Consists of RNA sequencing and exon microarray data profiling up to sixteen cortical and subcortical structures across full course of human brain development, high resolution neuroanatomical transcriptional profiles of about 300 distinct structures spanning entire brain for four midgestional prenatal specimens, in situ hybridization image data covering selected genes and brain regions in developing and adult human brain, reference atlas in full color with high resolution anatomic reference atlases of prenatal (two stages) and adult human brain along with supporting histology, magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) data.

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Human Nestin MAb (Clone 196908) (antibody)

RRID:AB_2251304

This monoclonal targets Human Nestin MAb (Clone 196908)

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HEK293 (cell line)

RRID:CVCL_0045

Cell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)

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HEK293T (cell line)

RRID:CVCL_0063

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

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