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Functionally Coherent Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling

Ian M. Overton, Andrew H. Sims, Jeremy A. Owen, Bret S. E. Heale, Matthew J. Ford, View ORCID ProfileAlexander L. R. Lubbock, Erola Pairo-Castineira, Abdelkader Essafi
doi: https://doi.org/10.1101/455709
Ian M. Overton
1MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
2Department of Systems Biology, Harvard University, Boston MA 02115, USA
3Centre for Synthetic and Systems Biology (SynthSys), University of Edinburgh, Edinburgh EH9 3BF, UK
4Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7AE, UK
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  • For correspondence: i.overton@qub.ac.uk
Andrew H. Sims
1MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
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Jeremy A. Owen
2Department of Systems Biology, Harvard University, Boston MA 02115, USA
5Department of Physics, Massachusetts Institute of Technology, Cambridge MA 02139, USA
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Bret S. E. Heale
1MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
6Intermountain Healthcare, 3930 River Walk, West Valley City UT 84120, USA
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Matthew J. Ford
1MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
7Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal H3A 0G4, Canada
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Alexander L. R. Lubbock
1MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
8Department of Biochemistry, Vanderbilt University, Nashville TN 37232, USA
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  • ORCID record for Alexander L. R. Lubbock
Erola Pairo-Castineira
1MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
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Abdelkader Essafi
1MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
9School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK
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Summary

Cell identity is governed by gene expression, regulated by Transcription Factor (TF) binding at cis-regulatory modules. We developed the NetNC software to decode the relationship between TF binding and the regulation of cognate target genes in cell decision-making; demonstrated on nine datasets for the Snail and Twist TFs, and also modENCODE ‘HOT’ regions. Results illuminated conserved molecular networks controlling development and disease, with implications for precision medicine. Predicted ‘neutral’ TF binding accounted for the majority (50% to ≥80%) of candidate target genes from statistically significant peaks and HOT regions had high functional coherence. Expression of orthologous functional TF targets discriminated breast cancer molecular subtypes and predicted novel tumour biology. We identified new gene functions and network modules including crosstalk with notch signalling and regulation of chromatin organisation, evidencing networks that reshape Waddington’s landscape during epithelial remodelling. Predicted invasion roles were validated using a tractable cell model, supporting our computational approach.

Footnotes

  • Co-author emails: Andrew H. Sims: andrew.sims{at}ed.ac.uk; Jeremy A. Owen: jeremyandrewowen{at}gmail.com; Bret S. E. Heale: bheale{at}gmail.com; Matthew J. Ford: matthew.ford{at}mail.mcgill.ca; Alexander L. R. Lubbock: alex.lubbock{at}vanderbilt.edu; Erola Pairo-Castineira: erola.pairo-castineira{at}igmm.ed.ac.uk; Abdelkader Essafi: a.essafi{at}bristol.ac.uk

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 15, 2019.
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Functionally Coherent Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling
Ian M. Overton, Andrew H. Sims, Jeremy A. Owen, Bret S. E. Heale, Matthew J. Ford, Alexander L. R. Lubbock, Erola Pairo-Castineira, Abdelkader Essafi
bioRxiv 455709; doi: https://doi.org/10.1101/455709
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Functionally Coherent Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling
Ian M. Overton, Andrew H. Sims, Jeremy A. Owen, Bret S. E. Heale, Matthew J. Ford, Alexander L. R. Lubbock, Erola Pairo-Castineira, Abdelkader Essafi
bioRxiv 455709; doi: https://doi.org/10.1101/455709

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