Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Pathol
2012 Nov 01;2283:274-85. doi: 10.1002/path.4082.
Show Gene links
Show Anatomy links
An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma.
Nelson AC, Pillay N, Henderson S, Presneau N, Tirabosco R, Halai D, Berisha F, Flicek P, Stemple DL, Stern CD, Wardle FC, Flanagan AM.
???displayArticle.abstract???
Chordoma is a rare malignant tumour of bone, the molecular marker of which is the expression of the transcription factor, brachyury. Having recently demonstrated that silencing brachyury induces growth arrest in a chordoma cell line, we now seek to identify its downstream target genes. Here we use an integrated functional genomics approach involving shRNA-mediated brachyury knockdown, gene expression microarray, ChIP-seq experiments, and bioinformatics analysis to achieve this goal. We confirm that the T-box binding motif of human brachyury is identical to that found in mouse, Xenopus, and zebrafish development, and that brachyury acts primarily as an activator of transcription. Using human chordoma samples for validation purposes, we show that brachyury binds 99 direct targets and indirectly influences the expression of 64 other genes, thereby acting as a master regulator of an elaborate oncogenic transcriptional network encompassing diverse signalling pathways including components of the cell cycle, and extracellular matrix components. Given the wide repertoire of its active binding and the relative specific localization of brachyury to the tumour cells, we propose that an RNA interference-based gene therapy approach is a plausible therapeutic avenue worthy of investigation.
Baker,
Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity.
2009, Pubmed
Baker,
Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity.
2009,
Pubmed Basso,
Reverse engineering of regulatory networks in human B cells.
2005,
Pubmed Brüderlein,
Molecular characterization of putative chordoma cell lines.
2010,
Pubmed Chi,
ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours.
2010,
Pubmed Dei Tos,
Unveiling the molecular pathogenesis of chordoma: a new paradigm for molecular targeting of rare cancers.
2011,
Pubmed Dewaele,
Frequent activation of EGFR in advanced chordomas.
2011,
Pubmed Dhar,
The CCN family proteins in carcinogenesis.
2010,
Pubmed Erwin,
The Notochord, Notochordal cell and CTGF/CCN-2: ongoing activity from development through maturation.
2008,
Pubmed Evans,
Genomic targets of Brachyury (T) in differentiating mouse embryonic stem cells.
2012,
Pubmed
,
Xenbase Fernando,
IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells.
2011,
Pubmed Fernando,
The T-box transcription factor Brachyury promotes epithelial-mesenchymal transition in human tumor cells.
2010,
Pubmed Fujikawa,
Tissue-specific regulation of the number of cell division rounds by inductive cell interaction and transcription factors during ascidian embryogenesis.
2011,
Pubmed Gentleman,
Bioconductor: open software development for computational biology and bioinformatics.
2004,
Pubmed Giardine,
Galaxy: a platform for interactive large-scale genome analysis.
2005,
Pubmed Goecks,
Galaxy: a comprehensive approach for supporting accessible, reproducible, and transparent computational research in the life sciences.
2010,
Pubmed Hallor,
Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation.
2008,
Pubmed Heaton,
Reflections on notochordal differentiation arising from a study of chordomas.
1985,
Pubmed Henderson,
A molecular map of mesenchymal tumors.
2005,
Pubmed Herrmann,
Expression pattern of the Brachyury gene in whole-mount TWis/TWis mutant embryos.
1991,
Pubmed Homminga,
Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia.
2011,
Pubmed Hotta,
Brachyury-downstream gene sets in a chordate, Ciona intestinalis: integrating notochord specification, morphogenesis and chordate evolution.
2008,
Pubmed Hsu,
Generation of chordoma cell line JHC7 and the identification of Brachyury as a novel molecular target.
2011,
Pubmed Jacobs,
Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers.
2000,
Pubmed Jacobs-Cohen,
Abnormalities of cells and extracellular matrix of T/T embryos.
1983,
Pubmed Johnson,
Adjusting batch effects in microarray expression data using empirical Bayes methods.
2007,
Pubmed Kelley,
Familial chordoma, a tumor of notochordal remnants, is linked to chromosome 7q33.
2001,
Pubmed Langmead,
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
2009,
Pubmed Launay,
Efficacy of epidermal growth factor receptor targeting in advanced chordoma: case report and literature review.
2011,
Pubmed Lewis,
Molecular classification of melanoma using real-time quantitative reverse transcriptase-polymerase chain reaction.
2005,
Pubmed Liberzon,
Molecular signatures database (MSigDB) 3.0.
2011,
Pubmed Livak,
Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
2001,
Pubmed Luo,
Highly parallel identification of essential genes in cancer cells.
2008,
Pubmed Mahony,
STAMP: a web tool for exploring DNA-binding motif similarities.
2007,
Pubmed Margolin,
ARACNE: an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context.
2006,
Pubmed Margolin,
Reverse engineering cellular networks.
2006,
Pubmed Matsunaga,
Aldo-Keto Reductase 1B10 and Its Role in Proliferation Capacity of Drug-Resistant Cancers.
2012,
Pubmed McMaster,
Chordoma: incidence and survival patterns in the United States, 1973-1995.
2001,
Pubmed Morley,
A gene regulatory network directed by zebrafish No tail accounts for its roles in mesoderm formation.
2009,
Pubmed Naiche,
T-box genes in vertebrate development.
2005,
Pubmed Ooi,
An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma.
2011,
Pubmed Palena,
The human T-box mesodermal transcription factor Brachyury is a candidate target for T-cell-mediated cancer immunotherapy.
2007,
Pubmed Park,
Sacral chordomas: Impact of high-dose proton/photon-beam radiation therapy combined with or without surgery for primary versus recurrent tumor.
2006,
Pubmed Pavesi,
Weeder Web: discovery of transcription factor binding sites in a set of sequences from co-regulated genes.
2004,
Pubmed Presneau,
Role of the transcription factor T (brachyury) in the pathogenesis of sporadic chordoma: a genetic and functional-based study.
2011,
Pubmed Raemaekers,
NuSAP, a novel microtubule-associated protein involved in mitotic spindle organization.
2003,
Pubmed Reich,
GenePattern 2.0.
2006,
Pubmed Ricke,
Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation.
2011,
Pubmed Salasznyk,
Adhesion to Vitronectin and Collagen I Promotes Osteogenic Differentiation of Human Mesenchymal Stem Cells.
2004,
Pubmed Salisbury,
Three-dimensional reconstruction of human embryonic notochords: clue to the pathogenesis of chordoma.
1993,
Pubmed Scheil,
Genome-wide analysis of sixteen chordomas by comparative genomic hybridization and cytogenetics of the first human chordoma cell line, U-CH1.
2001,
Pubmed Shalaby,
Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas.
2009,
Pubmed
,
Xenbase Shalaby,
The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target.
2011,
Pubmed Sleijfer,
The challenge of choosing appropriate end points in single-arm phase II studies of rare diseases.
2012,
Pubmed Smits,
Sox5 and Sox6 are required for notochord extracellular matrix sheath formation, notochord cell survival and development of the nucleus pulposus of intervertebral discs.
2003,
Pubmed Stacchiotti,
Phase II study of imatinib in advanced chordoma.
2012,
Pubmed Stemple,
Structure and function of the notochord: an essential organ for chordate development.
2005,
Pubmed Subramanian,
Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
2005,
Pubmed Szuhai,
'The chicken or the egg?' dilemma strikes back for the controlling mechanism in chordoma(#).
2012,
Pubmed Tada,
T-targets: clues to understanding the functions of T-box proteins.
2001,
Pubmed Tirabosco,
Brachyury expression in extra-axial skeletal and soft tissue chordomas: a marker that distinguishes chordoma from mixed tumor/myoepithelioma/parachordoma in soft tissue.
2008,
Pubmed Ueda,
Collagenous and basement membrane proteins of chordoma: immunohistochemical analysis.
1992,
Pubmed Vance,
Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas.
2005,
Pubmed Vance,
The retinoblastoma protein modulates Tbx2 functional specificity.
2010,
Pubmed Vujovic,
Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas.
2006,
Pubmed Wardle,
Zebrafish promoter microarrays identify actively transcribed embryonic genes.
2006,
Pubmed Whelan,
Incidence and survival of malignant bone sarcomas in England 1979-2007.
2012,
Pubmed Xu,
A signal-noise model for significance analysis of ChIP-seq with negative control.
2010,
Pubmed Yang,
T (brachyury) gene duplication confers major susceptibility to familial chordoma.
2009,
Pubmed Yu,
Epigenetic inactivation of T-box transcription factor 5, a novel tumor suppressor gene, is associated with colon cancer.
2010,
Pubmed Yu,
Integrin alpha 2 beta 1-dependent EGF receptor activation at cell-cell contact sites.
2000,
Pubmed
