The Oncogenic EWS-FLI1 Protein Binds In Vivo GGAA Microsatellite Sequences with Potential Transcriptional Activation Function
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{"title"=>"The oncogenic EWS-FLI1 protein binds in vivo GGAA microsatellite sequences with potential transcriptional activation function", "type"=>"journal", "authors"=>[{"first_name"=>"Noëlle", "last_name"=>"Guillon", "scopus_author_id"=>"26424620700"}, {"first_name"=>"Franck", "last_name"=>"Tirode", "scopus_author_id"=>"6506162940"}, {"first_name"=>"Valentina", "last_name"=>"Boeva", "scopus_author_id"=>"8967545100"}, {"first_name"=>"Andrei", "last_name"=>"Zynovyev", "scopus_author_id"=>"26424901600"}, {"first_name"=>"Emmanuel", "last_name"=>"Barillot", "scopus_author_id"=>"56273574000"}, {"first_name"=>"Olivier", "last_name"=>"Delattre", "scopus_author_id"=>"44060989000"}], "year"=>2009, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-63349090507", "doi"=>"10.1371/journal.pone.0004932", "sgr"=>"63349090507", "isbn"=>"1932-6203 (Electronic)", "pmid"=>"19305498", "issn"=>"19326203", "pui"=>"354396064"}, "id"=>"fec0b7dd-859f-3e43-83ad-ff3fb06702bc", "abstract"=>"The fusion between EWS and ETS family members is a key oncogenic event in Ewing tumors and important EWS-FLI1 target genes have been identified. However, until now, the search for EWS-FLI1 targets has been limited to promoter regions and no genome-wide comprehensive analysis of in vivo EWS-FLI1 binding sites has been undertaken. Using a ChIP-Seq approach to investigate EWS-FLI1-bound DNA sequences in two Ewing cell lines, we show that this chimeric transcription factor preferentially binds two types of sequences including consensus ETS motifs and microsatellite sequences. Most bound sites are found outside promoter regions. Microsatellites containing more than 9 GGAA repeats are very significantly enriched in EWS-FLI1 immunoprecipitates. Moreover, in reporter gene experiments, the transcription activation is highly dependent upon the number of repeats that are included in the construct. Importantly, in vivo EWS-FLI1-bound microsatellites are significantly associated with EWS-FLI1-driven gene activation. Put together, these results point out the likely contribution of microsatellite elements to long-distance transcription regulation and to oncogenesis.", "link"=>"http://www.mendeley.com/research/oncogenic-ewsfli1-protein-binds-vivo-ggaa-microsatellite-sequences-potential-transcriptional-activat", "reader_count"=>49, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>20, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>4, "Student > Bachelor"=>1, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>20, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>4, "Student > Bachelor"=>1, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>11, "Mathematics"=>1, "Agricultural and Biological Sciences"=>33, "Medicine and Dentistry"=>3, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>33}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>11}, "Mathematics"=>{"Mathematics"=>1}}, "reader_count_by_country"=>{"Canada"=>2, "Sweden"=>1, "United States"=>3, "United Kingdom"=>1, "France"=>1, "Australia"=>1, "Germany"=>1}, "group_count"=>3}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/447353", "https://ndownloader.figshare.com/files/447366", "https://ndownloader.figshare.com/files/447406"], "description"=>"<div><p>The fusion between EWS and ETS family members is a key oncogenic event in Ewing tumors and important EWS-FLI1 target genes have been identified. However, until now, the search for EWS-FLI1 targets has been limited to promoter regions and no genome-wide comprehensive analysis of <em>in vivo</em> EWS-FLI1 binding sites has been undertaken. Using a ChIP-Seq approach to investigate EWS-FLI1-bound DNA sequences in two Ewing cell lines, we show that this chimeric transcription factor preferentially binds two types of sequences including consensus ETS motifs and microsatellite sequences. Most bound sites are found outside promoter regions. Microsatellites containing more than 9 GGAA repeats are very significantly enriched in EWS-FLI1 immunoprecipitates. Moreover, in reporter gene experiments, the transcription activation is highly dependent upon the number of repeats that are included in the construct. Importantly, <em>in vivo</em> EWS-FLI1-bound microsatellites are significantly associated with EWS-FLI1-driven gene activation. Put together, these results point out the likely contribution of microsatellite elements to long-distance transcription regulation and to oncogenesis.</p></div>", "links"=>[], "tags"=>["oncogenic", "ews-fli1", "binds", "ggaa", "microsatellite", "sequences", "transcriptional", "activation"], "article_id"=>148161, "categories"=>["Genetics", "Cancer", "Biological Sciences"], "users"=>["Noëlle Guillon", "Franck Tirode", "Valentina Boeva", "Andrei Zynovyev", "Emmanuel Barillot", "Olivier Delattre"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0004932.s001", "https://dx.doi.org/10.1371/journal.pone.0004932.s002", "https://dx.doi.org/10.1371/journal.pone.0004932.s003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/The_Oncogenic_EWS_FLI1_Protein_Binds_In_Vivo_GGAA_Microsatellite_Sequences_with_Potential_Transcriptional_Activation_Function/148161", "title"=>"The Oncogenic EWS-FLI1 Protein Binds <em>In Vivo</em> GGAA Microsatellite Sequences with Potential Transcriptional Activation Function", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2009-03-23 02:16:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/903479"], "description"=>"<p>A. Enrichment of GGAA motifs in EWS-FLI1-bound sequences. Frequencies of each of 4096 possible 6mer nucleotides found for the 246 identified EWS-FLI1 specific regions (black circle) and for regions identified in the control experiment (white circle) are represented along the Y axis whereas frequency of the same 6mers in the genome is represented on the X axis. B. GGAA repeat enrichment is a common feature of Ewing cell lines. Number of sequences found in A673 (grey circle) and SK-N-MC (white circle) for each type of binding site. C. Consensus motif assessed with MEME algorithm (E-value = 4.1×10<sup>−46</sup>) in regions other than GGAA microsatellites.</p>", "links"=>[], "tags"=>["binds", "ggaa", "microsatellites", "ggaa-rich"], "article_id"=>573926, "categories"=>["Genetics", "Infectious Diseases", "Computational Biology", "Cancer"], "users"=>["Noëlle Guillon", "Franck Tirode", "Valentina Boeva", "Andrei Zynovyev", "Emmanuel Barillot", "Olivier Delattre"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0004932.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_EWS_FLI1_binds_GGAA_microsatellites_or_GGAA_rich_sequences_/573926", "title"=>"EWS-FLI1 binds GGAA microsatellites or GGAA-rich sequences.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-03-23 01:05:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/903562"], "description"=>"<p>A. Ratio of the number of GGAA repeats in EWS-FLI1-bound regions to the number of repeat in 50000 randomly picked regions. B. Ability of EWS-FLI1 to modulate transcription of a reporter gene depending upon the number of GGAA repeats. Firefly relative to Renilla luciferase activity is shown. Control experiments with the empty pGL3-promoter vector were set to 1.</p>", "links"=>[], "tags"=>["microsatellite"], "article_id"=>574019, "categories"=>["Genetics", "Infectious Diseases", "Computational Biology", "Cancer"], "users"=>["Noëlle Guillon", "Franck Tirode", "Valentina Boeva", "Andrei Zynovyev", "Emmanuel Barillot", "Olivier Delattre"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0004932.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_EWS_FLI1_microsatellite_length_preferences_/574019", "title"=>"EWS-FLI1 microsatellite length preferences.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-03-23 01:06:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/903648"], "description"=>"<p>A. Proportion of EWS-FLI1-bound regions, as compared to the proportion of random regions, around EWS-FLI1 regulated genes. The proportion of EWS-FLI1-bound regions as a function of the distance to the transcription start sites of EWS-FLI1-up or -down regulated genes (solid lines) is shown. As a control, a similar function is indicated for 1500 randomly chosen regions (dashed line). B. Gene Set Enrichment Analysis (GSEA) of genes flanking EWS-FLI1-bound microsatellites. The 94 genes flanking the 80 microsatellites>9R regions (upper panel) as well as the 144 genes flanking the non-microsatellites regions (lower panel) were used as gene set. The expression dataset resulted from previously described EWS-FLI1 inhibition experiments of A673 and SK-N-MC Ewing cell lines <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004932#pone.0004932-Tirode1\" target=\"_blank\">[37]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004932#pone.0004932-Smith1\" target=\"_blank\">[40]</a>, ranked using the signal-to-noise algorithm. A strong enrichment of genes flanking EWS-FLI1 bound GGAA microsatellites among EWS-FLI1 up-regulated genes is observed (upper panel). C–F. Regions upstream of EWS-FLI1 up-regulated genes are enriched in GGAA-microsatellites. The number of microsatellites with either 3 to 9 GGAA repeats (grey line) or more than 9 repeats (black line) was calculated for each 1 Kb window from 1 Kb to 1 Mb upstream of the transcription start sites. The numbers of GGAA repeats along DNA are shown for (C) 17000 known genes (control distribution), (D) 582 EWS-FLI1-up-regulated genes, (E) 558 EWS-FLI1-down-regulated genes and (F) 561 genes that are expressed in A673 and SK-N-MC cell lines but not regulated by EWS-FLI1. The control distribution shown in C is also indicated on part D, E and F.</p>", "links"=>[], "tags"=>["ews-fli1", "binding", "ggaa", "microsatellites"], "article_id"=>574100, "categories"=>["Genetics", "Infectious Diseases", "Computational Biology", "Cancer"], "users"=>["Noëlle Guillon", "Franck Tirode", "Valentina Boeva", "Andrei Zynovyev", "Emmanuel Barillot", "Olivier Delattre"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0004932.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Long_distance_EWS_FLI1_binding_on_GGAA_microsatellites_results_in_significant_gene_expression_activation_/574100", "title"=>"Long distance EWS-FLI1 binding on GGAA microsatellites results in significant gene expression activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-03-23 01:08:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/903796"], "description"=>"<p>(1) Compared to the genomic representation.</p>", "links"=>[], "tags"=>["sites", "enrichment", "regions", "ggaa"], "article_id"=>574249, "categories"=>["Genetics", "Infectious Diseases", "Computational Biology", "Cancer"], "users"=>["Noëlle Guillon", "Franck Tirode", "Valentina Boeva", "Andrei Zynovyev", "Emmanuel Barillot", "Olivier Delattre"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0004932.t002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transcription_factor_consensus_sites_enrichment_in_regions_other_than_GGAA_microsatellites_/574249", "title"=>"Transcription factor consensus sites enrichment in regions other than GGAA microsatellites.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-03-23 01:10:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/903839"], "description"=>"<p>(1) Compared to the genomic representation.</p>", "links"=>[], "tags"=>["modules", "containing", "etsf", "binding", "regions", "ggaa"], "article_id"=>574284, "categories"=>["Genetics", "Infectious Diseases", "Computational Biology", "Cancer"], "users"=>["Noëlle Guillon", "Franck Tirode", "Valentina Boeva", "Andrei Zynovyev", "Emmanuel Barillot", "Olivier Delattre"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0004932.t003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transcription_factor_modules_containing_an_ETSF_binding_site_in_regions_other_than_GGAA_microsatellites_/574284", "title"=>"Transcription factor modules containing an ETSF binding site in regions other than GGAA microsatellites.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-03-23 01:11:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/903880"], "description"=>"<p>Number of reads and corresponding mapped sequences per Chip-Seq experiments.</p>", "links"=>[], "tags"=>["reads", "corresponding", "mapped", "sequences", "ChIP-seq"], "article_id"=>574332, "categories"=>["Genetics", "Infectious Diseases", "Computational Biology", "Cancer"], "users"=>["Noëlle Guillon", "Franck Tirode", "Valentina Boeva", "Andrei Zynovyev", "Emmanuel Barillot", "Olivier Delattre"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0004932.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Number_of_reads_and_corresponding_mapped_sequences_per_Chip_Seq_experiments_/574332", "title"=>"Number of reads and corresponding mapped sequences per Chip-Seq experiments.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-03-23 01:12:12"}

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Relative Metric

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