An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma

J Pathol. 2012 Nov;228(3):274-85. doi: 10.1002/path.4082. Epub 2012 Sep 26.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / pathology
  • Bone Neoplasms / physiopathology*
  • Cell Cycle / physiology
  • Cell Differentiation / physiology
  • Cell Line, Tumor
  • Cell Proliferation
  • Chordoma / genetics*
  • Chordoma / pathology
  • Chordoma / physiopathology*
  • Fetal Proteins / genetics*
  • Fetal Proteins / physiology*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / physiology
  • Gene Knockdown Techniques
  • Genetic Therapy
  • Genomics*
  • Humans
  • Mice
  • Notochord / pathology
  • RNA Interference
  • T-Box Domain Proteins / genetics*
  • T-Box Domain Proteins / physiology*
  • Transcription, Genetic / physiology
  • Xenopus
  • Zebrafish


  • Fetal Proteins
  • T-Box Domain Proteins
  • Brachyury protein