Myxoid Liposarcoma-Associated EWSR1-DDIT3 Selectively Represses Osteoblastic and Chondrocytic Transcription in Multipotent Mesenchymal Cells
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{"title"=>"Myxoid liposarcoma-associated EWSR1-DDIT3 selectively represses osteoblastic and chondrocytic transcription in multipotent mesenchymal cells", "type"=>"journal", "authors"=>[{"first_name"=>"Kayo", "last_name"=>"Suzuki", "scopus_author_id"=>"55503675800"}, {"first_name"=>"Yoshito", "last_name"=>"Matsui", "scopus_author_id"=>"7402827426"}, {"first_name"=>"Mami", "last_name"=>"Higashimoto", "scopus_author_id"=>"55204673400"}, {"first_name"=>"Yoshiharu", "last_name"=>"Kawaguchi", "scopus_author_id"=>"7401964621"}, {"first_name"=>"Shoji", "last_name"=>"Seki", "scopus_author_id"=>"8589146900"}, {"first_name"=>"Hiraku", "last_name"=>"Motomura", "scopus_author_id"=>"24725175100"}, {"first_name"=>"Takeshi", "last_name"=>"Hori", "scopus_author_id"=>"55066627700"}, {"first_name"=>"Yasuhito", "last_name"=>"Yahara", "scopus_author_id"=>"14053138100"}, {"first_name"=>"Masahiko", "last_name"=>"Kanamori", "scopus_author_id"=>"7102427928"}, {"first_name"=>"Tomoatsu", "last_name"=>"Kimura", "scopus_author_id"=>"7405708537"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"22570737", "sgr"=>"84860523935", "doi"=>"10.1371/journal.pone.0036682", "scopus"=>"2-s2.0-84860523935", "pui"=>"364730443", "issn"=>"19326203"}, "id"=>"f2612245-3398-389f-aec9-b015f9bc644f", "abstract"=>"BACKGROUND: Liposarcomas are the most common class of soft tissue sarcomas, and myxoid liposarcoma is the second most common liposarcoma. EWSR1-DDIT3 is a chimeric fusion protein generated by the myxoid liposarcoma-specific chromosomal translocation t(12;22)(q13;q12). Current studies indicate that multipotent mesenchymal cells are the origin of sarcomas. The mechanism whereby EWSR1-DDIT3 contributes to the phenotypic selection of target cells during oncogenic transformation remains to be elucidated.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: Reporter assays showed that the EWSR1-DDIT3 myxoid liposarcoma fusion protein, but not its wild-type counterparts EWSR1 and DDIT3, selectively repressed the transcriptional activity of cell lineage-specific marker genes in multipotent mesenchymal C3H10T1/2 cells. Specifically, the osteoblastic marker Opn promoter and chondrocytic marker Col11a2 promoter were repressed, while the adipocytic marker Ppar-γ2 promoter was not affected. Mutation analyses, transient ChIP assays, and treatment of cells with trichostatin A (a potent inhibitor of histone deacetylases) or 5-Aza-2'-deoxycytidine (a methylation-resistant cytosine homolog) revealed the possible molecular mechanisms underlying the above-mentioned selective transcriptional repression. The first is a genetic action of the EWSR1-DDIT3 fusion protein, which results in binding to the functional C/EBP site within Opn and Col11a2 promoters through interaction of its DNA-binding domain and subsequent interference with endogenous C/EBPβ function. Another possible mechanism is an epigenetic action of EWSR1-DDIT3, which enhances histone deacetylation, DNA methylation, and histone H3K9 trimethylation at the transcriptional repression site. We hypothesize that EWSR1-DDIT3-mediated transcriptional regulation may modulate the target cell lineage through target gene-specific genetic and epigenetic conversions.\\n\\nCONCLUSIONS/SIGNIFICANCE: This study elucidates the molecular mechanisms underlying EWSR1-DDIT3 fusion protein-mediated phenotypic selection of putative target multipotent mesenchymal cells during myxoid liposarcoma development. A better understanding of this process is fundamental to the elucidation of possible direct lineage reprogramming in oncogenic sarcoma transformation mediated by fusion proteins.", "link"=>"http://www.mendeley.com/research/myxoid-liposarcomaassociated-ewsr1ddit3-selectively-represses-osteoblastic-chondrocytic-transcriptio", "reader_count"=>13, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Student > Doctoral Student"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>3, "Student > Master"=>1, "Other"=>1, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Student > Doctoral Student"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>3, "Student > Master"=>1, "Other"=>1, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>8, "Medicine and Dentistry"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>8}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Japan"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/643932"], "description"=>"<p>Transient ChIP assays using an antibody against C/EBPα, C/EBPβ, or normal IgG. C3H10T1/2 cells were transfected with Opn (<b>A</b>) and Col11a2 (<b>B</b>) luciferase reporter plasmids plus EWSR1-DDIT3 expression vectors. Promoter DNA fragments containing the C/EBP site (open box) were immunoprecipitated with an antibody against C/EBPα or C/EBPβ. Relative values reflecting protein–DNA interactions were calculated by adjusting corresponding signal intensities to those of input levels. Experiments in duplicate were repeated at least three times, and the results are shown as averages below each band. For C/EBPβ, the relative value of immunoprecipitated Opn and Col11a2 promoter fragments significantly decreased after EWSR1-DDIT3 overexpression from 0.71 to 0.30 and 0.76 to 0.35, respectively. Asterisks (*) indicate statistical significance (<i>p</i><0.05) calculated by unpaired <i>t</i>-test, with <i>p</i> values of 0.022 for Opn and 0.0025 for Col11a2. As indicated by the arrows, the forward PCR primers are promoter sequence-specific primers and locate upstream to the C/EBP site (open box), while the reverse PCR primer pGL3 is a plasmid-specific primer.</p>", "links"=>[], "tags"=>["affected", "recruitment", "endogenous", "opn", "col11a2"], "article_id"=>314412, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036682.g006", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_EWSR1_DDIT3_affected_recruitment_of_endogenous_C_EBP_946_to_the_C_EBP_site_within_Opn_and_Col11a2_promoters_/314412", "title"=>"EWSR1-DDIT3 affected recruitment of endogenous C/EBPβ to the C/EBP site within Opn and Col11a2 promoters.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:13:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/644216"], "description"=>"<p>(<b>A</b> and <b>B</b>) Effect of the DNA methylation-resistant cytosine analog 5-Aza-2′-deoxycytidine (AZA) on Opn (<b>A</b>) and Col11a2 (<b>B</b>) promoter activities. C3H10T1/2 cells in duplicate plates were cotransfected with promoter reporter plasmids plus EWSR1-DDIT3 expression vectors. Cells in one plate were assayed for luciferase activity 24 h after treatment with AZA and compared with the cells from the other plate that were not treated with AZA. Luciferase activities from AZA-treated cells relative to those from AZA-untreated cells are shown as fold derepression. Experiments in duplicate were repeated at least three times, and the results are shown as averages ± SE. An asterisk (*) indicates statistical significance (<i>p</i><0.05) calculated by unpaired <i>t</i>-test, with a <i>p</i> value of 0.0301 for Col11a2. N.S., not significant.</p>", "links"=>[], "tags"=>["derepression", "col11a2", "opn"], "article_id"=>314697, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036682.g008", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Significant_derepression_of_the_Col11a2_promoter_but_not_the_Opn_promoter_by_5_Aza_2_8242_deoxycytidine_/314697", "title"=>"Significant derepression of the Col11a2 promoter, but not the Opn promoter, by 5-Aza-2′-deoxycytidine.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:18:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/643388"], "description"=>"<p>(<b>A</b>) Schematic of domain structure of EWSR1, DDIT3, and EWSR1-DDIT3. SYQG-rich, Ser-Tyr-Gln-Gly-rich transactivating domain; RGG, regions with multiple Arg-Gly-Gly repeats; RNP-CS, ribonucleoprotein consensus sequence; TAD, transcriptional activation domain; BR, basic amino-acid-rich dimerization domain; LZ, leucine zipper DNA-binding domain. Asterisks (*) designate 27 amino acid residues originating from DNA sequences upstream of the translation start site of DDIT3 (broken line), which are translated after in-frame fusion to EWSR1. Arrows indicate points of fusion. (<b>B–D</b>) Effect of EWSR1-DDIT3, EWSR1, and DDIT3 expression vectors on the activities of Opn (<b>B</b>), Col11a2 (<b>C</b>), and Ppar-γ2 (<b>D</b>) promoter-luciferase constructs 48 h after transfection in C3H10T1/2 cells. EWSR1-DDIT3, but not its wild-type counterparts EWSR1 or DDIT3, repressed Opn and Col11a2 promoter activities. However, Ppar-γ2 promoter activity was not repressed. Transfection in duplicate was repeated at least three times, and the results are shown as averages ± SE. <i>p</i> values calculated by ANOVA were 0.001, 0.0159, and 0.005, for Opn, Col11a2, and Ppar-γ2, respectively. Asterisks (*) indicate statistical significance (<i>p</i><0.05) following Tukey–Kramer post-hoc test. N.S., not significant. (<b>E–G</b>) Human bone marrow-derived mesenchymal stem cells (hMSCs) were purchased from Lonza Corporation, Walkersville, MD, USA, and cultured in MSC growth media (MSCGM-CD™ BulletKit™, Lonza) with penicillin (100 U/ml), streptomycin (100 µg/ml), and amphotericin B (0.25 µg/ml) under 5% CO<sub>2</sub> at 37°C. Opn (<b>E</b>), Col11a2 (<b>F</b>), or Ppar-γ2 (<b>G</b>) promoter activity was analyzed from cell lysates extracted from cells cotransfected with pFLAG-CMV4 control, EWSR1-DDIT3, EWSR1, or DDIT3 48 h after transfection. These constructs were cotransfected with an internal control vector (Renilla). The luciferase activities were expressed as relative activity to that of the promoter-less reporter vector (pGL3 basic). Transfection in duplicate was repeated at least three times and the results are shown as average ± SE. <i>p</i> values calculated by ANOVA were 0.0445, <0.0001, and 0.2846, for Opn, Col11a2, and Ppar-γ2, respectively.</p>", "links"=>[], "tags"=>["fusion", "selectively", "repressed", "promoter", "activities", "lineage-specific", "genes", "cells"], "article_id"=>313862, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036682.g002", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_EWSR1_DDIT3_fusion_protein_selectively_repressed_promoter_activities_of_lineage_specific_marker_genes_in_C3H10T1_2_cells_as_well_as_in_hMSCs_/313862", "title"=>"EWSR1-DDIT3 fusion protein selectively repressed promoter activities of lineage-specific marker genes in C3H10T1/2 cells as well as in hMSCs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:04:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/643525"], "description"=>"<p>(<b>A</b>) Schematic drawing of EWSR1-DDIT3 and two mutants. SYQG-rich, Ser-Tyr-Gln-Gly-rich transactivating domain; TAD, transcriptional activation domain; BR, basic amino-acid-rich dimerization domain; LZ, leucine zipper dimerforming domain. Asterisks (*) designate 27 amino acid residues originating from DNA sequences upstream of the translation start site of DDIT3. EWSR1-DDIT3 del LZ lacks the entire LZ composed of 38 C-terminal amino acid residues (broken line). In EWSR1-DDIT3 mut LZ, all five leucine residues in LZ are converted to glycine residues, as designated. (<b>B</b> and <b>C</b>) Effect of EWSR1-DDIT3 or two forms of mutant expression vectors on the activities of Opn (<b>B</b>) and Col11a2 (<b>C</b>) promoter-luciferase constructs 48 h after transfection in C3H10T1/2 cells. Opn and Col11a2 promoter activities were significantly increased by EWSR1-DDIT3 del LZ and EWSR1-DDIT3 mut LZ than by EWSR1-DDIT3. Transfection in duplicate was repeated at least three times, and the results are shown as averages ± SE. <i>p</i> values calculated by ANOVA were 0.0001 for Opn and 0.0003 for Col11a2. Asterisks (*) indicate statistical significance (<i>p</i><0.05) following Tukey–Kramer post-hoc test.</p>", "links"=>[], "tags"=>["lz", "dimer", "forming", "was", "ewsr1-ddit3-mediated", "repression", "opn", "col11a2", "promoter"], "article_id"=>314001, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036682.g003", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Intact_LZ_dimer_forming_domain_was_essential_for_EWSR1_DDIT3_mediated_repression_of_Opn_and_Col11a2_promoter_activities_/314001", "title"=>"Intact LZ dimer forming domain was essential for EWSR1-DDIT3-mediated repression of Opn and Col11a2 promoter activities.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:06:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/644627"], "description"=>"<p>Primer Sets Used for RT-PCR.</p>", "links"=>[], "tags"=>["sets"], "article_id"=>315113, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036682.t001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Primer_Sets_Used_for_RT_PCR_/315113", "title"=>"Primer Sets Used for RT-PCR.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:25:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/644062"], "description"=>"<p>(<b>A</b> and <b>B</b>) Derepression of Opn (<b>A</b>) and Col11a2 (<b>B</b>) promoter activity by HDAC inhibitor, trichostatin A (TSA). C3H10T1/2 cells in duplicate plates were cotransfected with promoter reporter plasmids plus EWSR1-DDIT3 expression vectors. Cells in one plate were assayed for luciferase activity 24 h after treatment with TSA and compared with the cells from the other plate that were not treated with TSA. Luciferase activities from TSA-treated cells relative to those from TSA-untreated cells are shown as fold derepression. Experiments in duplicate were repeated at least three times, and the results are shown as averages ± SE. Asterisks (*) indicate statistical significance (<i>p</i><0.05) calculated by unpaired <i>t</i>-test, with <i>p</i> values of 0.0001 for Opn and 0.0277 for Col11a2. (<b>C</b> and <b>D</b>) Transient ChIP assays using an antibody against HDAC1 or normal IgG. C3H10T1/2 cells were transfected with Opn (<b>C</b>) and Col11a2 (<b>D</b>) luciferase reporter plasmids plus EWSR1-DDIT3 expression vectors. Promoter DNA fragments containing the C/EBP site (open box) were immunoprecipitated with an antibody against HDAC1. Relative values reflecting protein–DNA interactions were calculated by adjusting corresponding signal intensities to those of input levels. Experiments in duplicate were repeated at least three times, and the results are shown as averages below each band. Relative values of immunoprecipitated Opn and Col11a2 promoter fragments significantly increased after EWSR1-DDIT3 overexpression from 0.49 to 1.06 and 0.17 to 0.63, respectively. Asterisks (*) indicate statistical significance (<i>p</i><0.05) calculated by unpaired <i>t</i>-test, with <i>p</i> values of 0.0005 for Opn and 0.0021 for Col11a2. As indicated by the arrows, the forward PCR primers are promoter sequence-specific primers and locate upstream to the C/EBP site (open box), while the reverse PCR primer pGL3 is a plasmid-specific primer.</p>", "links"=>[], "tags"=>["histone", "deacetylases", "transcriptional", "repression", "opn", "col11a2", "promoters"], "article_id"=>314544, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036682.g007", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Involvement_of_histone_deacetylases_in_transcriptional_repression_of_Opn_and_Col11a2_promoters_by_EWSR1_DDIT3_/314544", "title"=>"Involvement of histone deacetylases in transcriptional repression of Opn and Col11a2 promoters by EWSR1-DDIT3.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:15:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/331691", "https://ndownloader.figshare.com/files/331723", "https://ndownloader.figshare.com/files/331755", "https://ndownloader.figshare.com/files/331786"], "description"=>"<div><h3>Background</h3><p>Liposarcomas are the most common class of soft tissue sarcomas, and myxoid liposarcoma is the second most common liposarcoma. EWSR1-DDIT3 is a chimeric fusion protein generated by the myxoid liposarcoma-specific chromosomal translocation t(12;22)(q13;q12). Current studies indicate that multipotent mesenchymal cells are the origin of sarcomas. The mechanism whereby EWSR1-DDIT3 contributes to the phenotypic selection of target cells during oncogenic transformation remains to be elucidated.</p> <h3>Methodology/Principal Findings</h3><p>Reporter assays showed that the EWSR1-DDIT3 myxoid liposarcoma fusion protein, but not its wild-type counterparts EWSR1 and DDIT3, selectively repressed the transcriptional activity of cell lineage-specific marker genes in multipotent mesenchymal C3H10T1/2 cells. Specifically, the osteoblastic marker Opn promoter and chondrocytic marker Col11a2 promoter were repressed, while the adipocytic marker Ppar-γ2 promoter was not affected. Mutation analyses, transient ChIP assays, and treatment of cells with trichostatin A (a potent inhibitor of histone deacetylases) or 5-Aza-2′-deoxycytidine (a methylation-resistant cytosine homolog) revealed the possible molecular mechanisms underlying the above-mentioned selective transcriptional repression. The first is a genetic action of the EWSR1-DDIT3 fusion protein, which results in binding to the functional C/EBP site within Opn and Col11a2 promoters through interaction of its DNA-binding domain and subsequent interference with endogenous C/EBPβ function. Another possible mechanism is an epigenetic action of EWSR1-DDIT3, which enhances histone deacetylation, DNA methylation, and histone H3K9 trimethylation at the transcriptional repression site. We hypothesize that EWSR1-DDIT3-mediated transcriptional regulation may modulate the target cell lineage through target gene-specific genetic and epigenetic conversions.</p> <h3>Conclusions/Significance</h3><p>This study elucidates the molecular mechanisms underlying EWSR1-DDIT3 fusion protein-mediated phenotypic selection of putative target multipotent mesenchymal cells during myxoid liposarcoma development. A better understanding of this process is fundamental to the elucidation of possible direct lineage reprogramming in oncogenic sarcoma transformation mediated by fusion proteins.</p> </div>", "links"=>[], "tags"=>["myxoid", "liposarcoma-associated", "ewsr1-ddit3", "selectively", "represses", "osteoblastic", "chondrocytic", "transcription", "multipotent", "mesenchymal", "cells"], "article_id"=>125486, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0036682.s001", "https://dx.doi.org/10.1371/journal.pone.0036682.s002", "https://dx.doi.org/10.1371/journal.pone.0036682.s003", "https://dx.doi.org/10.1371/journal.pone.0036682.s004"], "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Myxoid_Liposarcoma_Associated_EWSR1_DDIT3_Selectively_Represses_Osteoblastic_and_Chondrocytic_Transcription_in_Multipotent_Mesenchymal_Cells/125486", "title"=>"Myxoid Liposarcoma-Associated EWSR1-DDIT3 Selectively Represses Osteoblastic and Chondrocytic Transcription in Multipotent Mesenchymal Cells", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-05-03 01:31:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/643628"], "description"=>"<p>(<b>A</b>) An inverted CCAAT box (boxed) of the pGL3-Opn promoter construct was mutated as designated to produce pGL3-Opn mut. The pGL3-Opn mut exhibited significantly reduced promoter activity. (<b>B</b>) A half C/EBP site (boxed) of the pGL3-Col11a2 promoter construct was mutated as designated to produce pGL3-Col11a2 mut. The pGL3-Col11a2 mut exhibited significantly reduced promoter activity. (<b>C</b>) The pGL3-Ppar-γ2 promoter construct containing tandem repeats of C/EBP-binding sites (boxed) and its deletion mutants, pGL3-334 (lacking the distal C/EBP binding site I) and pGL3-320 (lacking both C/EBP-binding sites I and II), exhibited comparable activity. The luciferase activities were expressed as fold inductions; each activity relative to that of the promoter-less reporter vector (pGL3 basic). Transfection in duplicate was repeated at least three times, and the results are shown as averages ± SE. Asterisks (*) indicate statistical significance (<i>p</i><0.05) calculated by unpaired t-test.</p>", "links"=>[], "tags"=>["sites", "opn", "col11a2", "promoters"], "article_id"=>314111, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036682.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Identification_of_potential_C_EBP_binding_sites_within_Opn_and_Col11a2_promoters_in_C3H10T1_2_cells_/314111", "title"=>"Identification of potential C/EBP-binding sites within Opn and Col11a2 promoters in C3H10T1/2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:08:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/644334"], "description"=>"<p>Transient ChIP assays using an antibody against acetylated H3K9 or trimethylated H3K9. C3H10T1/2 cells were transfected with Opn (<b>A</b>) and Col11a2 (<b>B</b>) luciferase reporter plasmids plus EWSR1-DDIT3 expression vectors. Promoter DNA fragments around C/EBP site were immunoprecipitated with an antibody against acetylated H3K9 (H3K9-Ace) or trimethylated H3K9 (H3K9-Met) (top panels). Relative values reflecting protein–DNA interactions were calculated by adjusting corresponding signal intensities to those of input levels. Experiments in duplicate were repeated at least three times, and EWSR1-DDIT3-mediated changes in relative values are shown as averages ± SE (bottom panels). (<b>C</b>) Ratio of H3K9-Ace versus H3K9-Met around Opn and Col11a2 promoter constructs. Error bars indicate SE. Asterisks (*) indicate statistical significance (<i>p</i><0.05) calculated by unpaired <i>t</i>-test. N.S., not significant.</p>", "links"=>[], "tags"=>["influenced", "levels", "acetylation", "trimethylation", "h3k9", "opn", "col11a2"], "article_id"=>314808, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036682.g009", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_EWSR1_DDIT3_influenced_the_levels_of_acetylation_or_trimethylation_at_H3K9_around_Opn_and_Col11a2_promoters_/314808", "title"=>"EWSR1-DDIT3 influenced the levels of acetylation or trimethylation at H3K9 around Opn and Col11a2 promoters.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:20:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/643797"], "description"=>"<p>Transient ChIP assays using an antibody against the N-terminal FLAG epitope or normal IgG. C3H10T1/2 cells were transfected with Opn (<b>A</b>) or Col11a2 (<b>B</b>) luciferase reporter plasmids plus FLAG-tagged expression vectors. Promoter DNA fragments containing potential C/EBP-binding sites (open box) were immunoprecipitated with EWSR1-DDIT3 when wild-type Opn (pGL3-Opn) and Col11a2 (pGL3-Col11a2) promoter constructs were analyzed. Either deleting (EWSR1-DDIT3 del LZ, broken line) or mutating (EWSR1-DDIT3 mut LZ, filled box) the LZ dimer forming domain of EWSR1-DDIT3 or mutating potential C/EBP-binding sites within Opn (inverted CCAAT box, pGL3-Opn mut, filled box) and Col11a2 (half C/EBP site, pGL3-Col11a2 mut, filled box) promoters eliminated the protein–DNA interaction. As indicated by the arrows, the forward PCR primers are promoter sequence-specific primers and locate upstream to the potential C/EBP-binding site (open box), while the reverse PCR primer pGL3 is a plasmid-specific primer.</p>", "links"=>[], "tags"=>["ewsr1-ddit3", "sites", "opn", "col11a2", "promoters"], "article_id"=>314277, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036682.g005", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Interaction_of_EWSR1_DDIT3_and_potential_C_EBP_binding_sites_within_Opn_and_Col11a2_promoters_in_vivo_/314277", "title"=>"Interaction of EWSR1-DDIT3 and potential C/EBP-binding sites within Opn and Col11a2 promoters <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:11:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/644549"], "description"=>"<p>Western blotting using an antibody against the N-terminal FLAG epitope tag. Each protein band is indicated by an asterisk (*).</p>", "links"=>[], "tags"=>["flag-tagged"], "article_id"=>315039, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036682.g011", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Protein_expression_by_each_FLAG_tagged_expression_vector_/315039", "title"=>"Protein expression by each FLAG-tagged expression vector.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:23:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/643281"], "description"=>"<p>RT-PCR analysis detected osteoblastic marker Opn (lane 1), chondrocytic marker Col11a2 (lane 3), and adipocytic marker Ppar-γ (lane 5) mRNA transcripts in C3H10T1/2 cells. Mouse osteosarcoma cell line LM8 (lane 2), mouse embryonic skeleton cells (lane 4), and mouse preadipocytic cell line 3T3-L1 (lane 6) were analyzed as positive controls for Opn, Col11a2, and Ppar-γ gene expression, respectively. The β-actin transcript level served as a loading control for each reaction.</p>", "links"=>[], "tags"=>["multipotent", "mesenchymal", "cells", "lineage-specific"], "article_id"=>313761, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036682.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Innate_mouse_multipotent_mesenchymal_C3H10T1_2_cells_expressed_multiple_lineage_specific_marker_genes_/313761", "title"=>"Innate mouse multipotent mesenchymal C3H10T1/2 cells expressed multiple lineage-specific marker genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:02:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/644474"], "description"=>"<p>(<b>A</b>) Direct lineage reprogramming of multipotent mesenchymal cells (MMC) by EWSR1-DDIT3. (<b>B</b>) Genetic action of EWSR1-DDIT3, which binds to the functional C/EBP site within target promoters through interaction of its DNA-binding domain and interferes with endogenous C/EBPβ function. (<b>C</b>) Epigenetic action introduced by EWSR1-DDIT3, enhancing histone deacetylation, DNA methylation, and histone 3 (H3) lysine 9 (K9) trimethylation at the transcriptional repression site. Tf, transcription factor; Ace, acetylation; CpG, cytosine–guanine dinucleotide; HAT, histone acetyltransferase; HDAC, histone deacetylases; HMT, histone methyltransferases; DNMT, DNA methyltransferases; Met, methylation; TMZ, temozolomide.</p>", "links"=>[], "tags"=>["diagram", "mechanisms", "ewsr1-ddit3", "exerts", "selective", "transcriptional", "repression", "multipotent", "mesenchymal"], "article_id"=>314943, "categories"=>["Cancer", "Molecular Biology", "Cell Biology"], "users"=>["Kayo Suzuki", "Yoshito Matsui", "Mami Higashimoto", "Yoshiharu Kawaguchi", "Shoji Seki", "Hiraku Motomura", "Takeshi Hori", "Yasuhito Yahara", "Masahiko Kanamori", "Tomoatsu Kimura"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036682.g010", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hypothetical_diagram_showing_mechanisms_by_which_EWSR1_DDIT3_exerts_selective_transcriptional_repression_in_multipotent_mesenchymal_cells_/314943", "title"=>"Hypothetical diagram showing mechanisms by which EWSR1-DDIT3 exerts selective transcriptional repression in multipotent mesenchymal cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:22:23"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2012-01-01T00:00:00Z", "end_date"=>"2012-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences", "average_usage"=>[322, 550, 671, 773, 864, 955, 1048, 1135, 1223, 1308, 1387, 1465, 1534, 1602, 1673, 1744, 1813, 1885, 1955, 2026, 2093, 2160, 2228, 2290, 2349]}, {"subject_area"=>"/Biology and life sciences/Biochemistry", "average_usage"=>[316, 541, 663, 766, 856, 950, 1041, 1128, 1218, 1302, 1382, 1456, 1526, 1593, 1657, 1729, 1796, 1862, 1930, 1999, 2065, 2132, 2202, 2261, 2319]}, {"subject_area"=>"/Biology and life sciences/Cell biology", "average_usage"=>[319, 556, 679, 785, 881, 970, 1062, 1149, 1236, 1323, 1402, 1474, 1545, 1617, 1681, 1754, 1822, 1892, 1963, 2031, 2099, 2165, 2233, 2299, 2359]}]}
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