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
