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An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma
- Source :
- The Journal of pathology. 228(3)
- Publication Year :
- 2012
-
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.
- Subjects :
- Fetal Proteins
Transcription, Genetic
Gene Expression Profiling
Xenopus
Cell Cycle
Notochord
Bone Neoplasms
Cell Differentiation
Genetic Therapy
Genomics
Article
Gene Expression Regulation, Neoplastic
Mice
Cell Line, Tumor
Gene Knockdown Techniques
Chordoma
Animals
Humans
RNA Interference
T-Box Domain Proteins
Zebrafish
Cell Proliferation
Subjects
Details
- ISSN :
- 10969896
- Volume :
- 228
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- The Journal of pathology
- Accession number :
- edsair.pmid.dedup....bf5f7267b4f18f9513c734bc3a4e83ac