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1.  Small Molecules Dorsomorphin and LDN-193189 Inhibit Myostatin/GDF8 Signaling and Promote Functional Myoblast Differentiation* 
The Journal of Biological Chemistry  2014;290(6):3390-3404.
Background: GDF8/myostatin suppresses myogenic differentiation.
Results: The small molecule inhibitors dorsomorphin and LDN-193189 bind to and inhibit the GDF8 receptor ActRII and ALK4.
Conclusion: Dorsomorphin and LDN-193189 promote myogenesis in vitro.
Significance: Detailed molecular characterization of small molecule inhibitors targeting the GDF8/myostatin pathway demonstrates their potential and risk when applied to promote muscle development.
GDF8, or myostatin, is a member of the TGF-β superfamily of secreted polypeptide growth factors. GDF8 is a potent negative regulator of myogenesis both in vivo and in vitro. We found that GDF8 signaling was inhibited by the small molecule ATP competitive inhibitors dorsomorphin and LDN-193189. These compounds were previously shown to be potent inhibitors of BMP signaling by binding to the BMP type I receptors ALK1/2/3/6. We present the crystal structure of the type II receptor ActRIIA with dorsomorphin and demonstrate that dorsomorphin or LDN-193189 target GDF8 induced Smad2/3 signaling and repression of myogenic transcription factors. As a result, both inhibitors rescued myogenesis in myoblasts treated with GDF8. As revealed by quantitative live cell microscopy, treatment with dorsomorphin or LDN-193189 promoted the contractile activity of myotubular networks in vitro. We therefore suggest these inhibitors as suitable tools to promote functional myogenesis.
doi:10.1074/jbc.M114.604397
PMCID: PMC4319009  PMID: 25368322
Bone Morphogenetic Protein (BMP); Myogenesis; Myostatin; Serine/Threonine Protein Kinase; Small Molecule
2.  Expression Atlas update—a database of gene and transcript expression from microarray- and sequencing-based functional genomics experiments 
Nucleic Acids Research  2013;42(Database issue):D926-D932.
Expression Atlas (http://www.ebi.ac.uk/gxa) is a value-added database providing information about gene, protein and splice variant expression in different cell types, organism parts, developmental stages, diseases and other biological and experimental conditions. The database consists of selected high-quality microarray and RNA-sequencing experiments from ArrayExpress that have been manually curated, annotated with Experimental Factor Ontology terms and processed using standardized microarray and RNA-sequencing analysis methods. The new version of Expression Atlas introduces the concept of ‘baseline’ expression, i.e. gene and splice variant abundance levels in healthy or untreated conditions, such as tissues or cell types. Differential gene expression data benefit from an in-depth curation of experimental intent, resulting in biologically meaningful ‘contrasts’, i.e. instances of differential pairwise comparisons between two sets of biological replicates. Other novel aspects of Expression Atlas are its strict quality control of raw experimental data, up-to-date RNA-sequencing analysis methods, expression data at the level of gene sets, as well as genes and a more powerful search interface designed to maximize the biological value provided to the user.
doi:10.1093/nar/gkt1270
PMCID: PMC3964963  PMID: 24304889
3.  ArrayExpress update—trends in database growth and links to data analysis tools 
Nucleic Acids Research  2012;41(Database issue):D987-D990.
The ArrayExpress Archive of Functional Genomics Data (http://www.ebi.ac.uk/arrayexpress) is one of three international functional genomics public data repositories, alongside the Gene Expression Omnibus at NCBI and the DDBJ Omics Archive, supporting peer-reviewed publications. It accepts data generated by sequencing or array-based technologies and currently contains data from almost a million assays, from over 30 000 experiments. The proportion of sequencing-based submissions has grown significantly over the last 2 years and has reached, in 2012, 15% of all new data. All data are available from ArrayExpress in MAGE-TAB format, which allows robust linking to data analysis and visualization tools, including Bioconductor and GenomeSpace. Additionally, R objects, for microarray data, and binary alignment format files, for sequencing data, have been generated for a significant proportion of ArrayExpress data.
doi:10.1093/nar/gks1174
PMCID: PMC3531147  PMID: 23193272
4.  Gene Expression Atlas update—a value-added database of microarray and sequencing-based functional genomics experiments 
Nucleic Acids Research  2011;40(Database issue):D1077-D1081.
Gene Expression Atlas (http://www.ebi.ac.uk/gxa) is an added-value database providing information about gene expression in different cell types, organism parts, developmental stages, disease states, sample treatments and other biological/experimental conditions. The content of this database derives from curation, re-annotation and statistical analysis of selected data from the ArrayExpress Archive and the European Nucleotide Archive. A simple interface allows the user to query for differential gene expression either by gene names or attributes or by biological conditions, e.g. diseases, organism parts or cell types. Since our previous report we made 20 monthly releases and, as of Release 11.08 (August 2011), the database supports 19 species, which contains expression data measured for 19 014 biological conditions in 136 551 assays from 5598 independent studies.
doi:10.1093/nar/gkr913
PMCID: PMC3245177  PMID: 22064864
5.  ArrayExpress update—an archive of microarray and high-throughput sequencing-based functional genomics experiments 
Nucleic Acids Research  2010;39(Database issue):D1002-D1004.
The ArrayExpress Archive (http://www.ebi.ac.uk/arrayexpress) is one of the three international public repositories of functional genomics data supporting publications. It includes data generated by sequencing or array-based technologies. Data are submitted by users and imported directly from the NCBI Gene Expression Omnibus. The ArrayExpress Archive is closely integrated with the Gene Expression Atlas and the sequence databases at the European Bioinformatics Institute. Advanced queries provided via ontology enabled interfaces include queries based on technology and sample attributes such as disease, cell types and anatomy.
doi:10.1093/nar/gkq1040
PMCID: PMC3013660  PMID: 21071405
6.  Gene Expression Atlas at the European Bioinformatics Institute 
Nucleic Acids Research  2009;38(Database issue):D690-D698.
The Gene Expression Atlas (http://www.ebi.ac.uk/gxa) is an added-value database providing information about gene expression in different cell types, organism parts, developmental stages, disease states, sample treatments and other biological/experimental conditions. The content of this database derives from curation, re-annotation and statistical analysis of selected data from the ArrayExpress Archive of Functional Genomics Data. A simple interface allows the user to query for differential gene expression either (i) by gene names or attributes such as Gene Ontology terms, or (ii) by biological conditions, e.g. diseases, organism parts or cell types. The gene queries return the conditions where expression has been reported, while condition queries return which genes are reported to be expressed in these conditions. A combination of both query types is possible. The query results are ranked using various statistical measures and by how many independent studies in the database show the particular gene-condition association. Currently, the database contains information about more than 200 000 genes from nine species and almost 4500 biological conditions studied in over 30 000 assays from over 1000 independent studies.
doi:10.1093/nar/gkp936
PMCID: PMC2808905  PMID: 19906730
7.  ArrayExpress update—from an archive of functional genomics experiments to the atlas of gene expression 
Nucleic Acids Research  2008;37(Database issue):D868-D872.
ArrayExpress http://www.ebi.ac.uk/arrayexpress consists of three components: the ArrayExpress Repository—a public archive of functional genomics experiments and supporting data, the ArrayExpress Warehouse—a database of gene expression profiles and other bio-measurements and the ArrayExpress Atlas—a new summary database and meta-analytical tool of ranked gene expression across multiple experiments and different biological conditions. The Repository contains data from over 6000 experiments comprising approximately 200 000 assays, and the database doubles in size every 15 months. The majority of the data are array based, but other data types are included, most recently—ultra high-throughput sequencing transcriptomics and epigenetic data. The Warehouse and Atlas allow users to query for differentially expressed genes by gene names and properties, experimental conditions and sample properties, or a combination of both. In this update, we describe the ArrayExpress developments over the last two years.
doi:10.1093/nar/gkn889
PMCID: PMC2686529  PMID: 19015125
8.  MAGETabulator, a suite of tools to support the microarray data format MAGE-TAB 
Bioinformatics  2008;25(2):279-280.
Summary: The MAGE-TAB format for microarray data representation and exchange has been proposed by the microarray community to replace the more complex MAGE-ML format. We present a suite of tools to support MAGE-TAB generation and validation, conversion between existing formats for data exchange, visualization of the experiment designs encoded by MAGE-TAB documents and the mining of such documents for semantic content.
Availability: Software is available from http://tab2mage.sourceforge.net/
Contact: tfrayner@gmail.com
doi:10.1093/bioinformatics/btn617
PMCID: PMC2638998  PMID: 19038988
9.  Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication 
Nature  2005;437(7055):94-100.
Human subtelomeres are polymorphic patchworks of inter-chromosomal segmental duplications at the ends of chromosomes. We provide evidence here that these patchworks arose recently through repeated translocations between chromosome ends. We assess the relative contribution of the major modes of ectopic DNA repair to the formation of subtelomeric duplications and find that non-homologous end-joining predominates. Once subtelomeric duplications arise, they are prone to homology-based sequence transfers as evidenced by incongruent phylogenetic relationships of neighboring sections. Inter-chromosomal recombination of subtelomeres is a potent force for recent change. Cytogenetic and sequence analyses reveal that pieces of the subtelomeric patchwork changed location and copy number during primate evolution with unprecedented frequency. Half of known subtelomeric sequence formed recently through human-specific sequence transfers and duplications. Subtelomeric dynamics result in a gene-duplication rate significantly higher than the genome average and could have both advantageous and pathological consequences in human biology. More generally, our analyses suggest an evolutionary cycle between segmental polymorphisms and genome rearrangements.
doi:10.1038/nature04029
PMCID: PMC1368961  PMID: 16136133
10.  Odorant receptor expressed sequence tags demonstrate olfactory expression of over 400 genes, extensive alternate splicing and unequal expression levels 
Genome Biology  2003;4(11):R71.
Previous computational analyses have identified approximately 1,500 mouse olfactory receptors, but experimental evidence confirming olfactory function is available for very few receptors. A mouse olfactory epithelium cDNA library was screened to obtain olfactory receptor expressed sequence tags, providing evidence of olfactory function for many additional olfactory receptors, as well as identifying gene structure and putative promoter regions.
Background
The olfactory receptor gene family is one of the largest in the mammalian genome. Previous computational analyses have identified approximately 1,500 mouse olfactory receptors, but experimental evidence confirming olfactory function is available for very few olfactory receptors. We therefore screened a mouse olfactory epithelium cDNA library to obtain olfactory receptor expressed sequence tags, providing evidence of olfactory function for many additional olfactory receptors, as well as identifying gene structure and putative promoter regions.
Results
We identified more than 1,200 odorant receptor cDNAs representing more than 400 genes. Using real-time PCR to confirm expression level differences suggested by our screen, we find that transcript levels in the olfactory epithelium can differ between olfactory receptors by up to 300-fold. Differences for one gene pair are apparently due to both unequal numbers of expressing cells and unequal transcript levels per expressing cell. At least two-thirds of olfactory receptors exhibit multiple transcriptional variants, with alternative isoforms of both 5' and 3' untranslated regions. Some transcripts (5%) utilize splice sites within the coding region, contrary to the stereotyped olfactory receptor gene structure. Most atypical transcripts encode nonfunctional olfactory receptors, but can occasionally increase receptor diversity.
Conclusions
Our cDNA collection confirms olfactory function of over one-third of the intact mouse olfactory receptors. Most of these genes were previously annotated as olfactory receptors based solely on sequence similarity. Our finding that different olfactory receptors have different expression levels is intriguing given the one-neuron, one-gene expression regime of olfactory receptors. We provide 5' untranslated region sequences and candidate promoter regions for more than 300 olfactory receptors, valuable resources for computational regulatory motif searches and for designing olfactory receptor microarrays and other experimental probes.
PMCID: PMC329117  PMID: 14611657

Results 1-10 (10)