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

Andrew C. Nelson; Nischalan Pillay; Stephen Henderson; Nadege Presneau; Roberto Tirabosco; Dina Halai; Fitim Berisha; Paul Flicek; Derek L. Stemple; Claudio D. Stern; Fiona C. Wardle; Adrienne M. Flanagan

doi:10.1002/path.4082

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

Andrew C. Nelson, Nischalan Pillay, Stephen Henderson, Nadege Presneau, Roberto Tirabosco, Dina Halai, Fitim Berisha, Paul Flicek, Derek L. Stemple, Claudio D. Stern, Fiona C. Wardle, Adrienne M. Flanagan

Research output: Contribution to journal › Article › peer-review

79 Citations (Scopus)

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. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Original language	English
Pages (from-to)	274-285
Number of pages	12
Journal	Journal of Pathology
Volume	228
Issue number	3
DOIs	https://doi.org/10.1002/path.4082
Publication status	Published - Nov 2012

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@article{b869956b402f49c1bb99ac3eceda6df4,

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

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. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",

author = "Nelson, {Andrew C.} and Nischalan Pillay and Stephen Henderson and Nadege Presneau and Roberto Tirabosco and Dina Halai and Fitim Berisha and Paul Flicek and Stemple, {Derek L.} and Stern, {Claudio D.} and Wardle, {Fiona C.} and Flanagan, {Adrienne M.}",

year = "2012",

month = nov,

doi = "10.1002/path.4082",

language = "English",

volume = "228",

pages = "274--285",

journal = "Journal of Pathology",

issn = "0022-3417",

publisher = "Pathological Society of Great Britain and Ireland",

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T1 - An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma

AU - Nelson, Andrew C.

AU - Pillay, Nischalan

AU - Henderson, Stephen

AU - Presneau, Nadege

AU - Tirabosco, Roberto

AU - Halai, Dina

AU - Berisha, Fitim

AU - Flicek, Paul

AU - Stemple, Derek L.

AU - Stern, Claudio D.

AU - Wardle, Fiona C.

AU - Flanagan, Adrienne M.

PY - 2012/11

Y1 - 2012/11

N2 - 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. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

AB - 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. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

U2 - 10.1002/path.4082

DO - 10.1002/path.4082

M3 - Article

SN - 0022-3417

VL - 228

SP - 274

EP - 285

JO - Journal of Pathology

JF - Journal of Pathology

IS - 3

ER -

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

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