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Article

Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling

1
MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
2
Department of Systems Biology, Harvard University, Boston, MA 02115, USA
3
Centre for Synthetic and Systems Biology (SynthSys), University of Edinburgh, Edinburgh EH9 3BF, UK
4
Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, UK
5
Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
*
Author to whom correspondence should be addressed.
Current address: Intermountain Healthcare, 3930 River Walk, West Valley City, UT 84120, USA.
Current address: Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 0G4, Canada.
§
Current address: Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
Current address: School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
Cancers 2020, 12(10), 2823; https://doi.org/10.3390/cancers12102823
Received: 9 August 2020 / Revised: 16 September 2020 / Accepted: 24 September 2020 / Published: 30 September 2020
(This article belongs to the Special Issue Cancer Modeling and Network Biology)
Cell identity is governed by gene expression, regulated by transcription factor (TF) binding at cis-regulatory modules. Decoding the relationship between TF binding patterns and gene regulation is nontrivial, remaining a fundamental limitation in understanding cell decision-making. We developed the NetNC software to predict functionally active regulation of TF targets; demonstrated on nine datasets for the TFs Snail, Twist, and modENCODE Highly Occupied Target (HOT) regions. Snail and Twist are canonical drivers of epithelial to mesenchymal transition (EMT), a cell programme important in development, tumour progression and fibrosis. Predicted “neutral” (non-functional) TF binding always accounted for the majority (50% to 95%) of candidate target genes from statistically significant peaks and HOT regions had higher functional binding than most of the Snail and Twist datasets examined. Our results illuminated conserved gene networks that control epithelial plasticity in development and disease. We identified new gene functions and network modules including crosstalk with notch signalling and regulation of chromatin organisation, evidencing networks that reshape Waddington’s epigenetic landscape during epithelial remodelling. Expression of orthologous functional TF targets discriminated breast cancer molecular subtypes and predicted novel tumour biology, with implications for precision medicine. Predicted invasion roles were validated using a tractable cell model, supporting our approach. View Full-Text
Keywords: network biology; ChIP-seq; breast cancer; transcription factors; EMT; functional gene network; mesoderm; Drosophila melanogaster; gene regulation; epithelial remodelling network biology; ChIP-seq; breast cancer; transcription factors; EMT; functional gene network; mesoderm; Drosophila melanogaster; gene regulation; epithelial remodelling
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MDPI and ACS Style

Overton, I.M.; Sims, A.H.; Owen, J.A.; Heale, B.S.E.; Ford, M.J.; Lubbock, A.L.R.; Pairo-Castineira, E.; Essafi, A. Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling. Cancers 2020, 12, 2823. https://doi.org/10.3390/cancers12102823

AMA Style

Overton IM, Sims AH, Owen JA, Heale BSE, Ford MJ, Lubbock ALR, Pairo-Castineira E, Essafi A. Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling. Cancers. 2020; 12(10):2823. https://doi.org/10.3390/cancers12102823

Chicago/Turabian Style

Overton, Ian M., Andrew H. Sims, Jeremy A. Owen, Bret S.E. Heale, Matthew J. Ford, Alexander L.R. Lubbock, Erola Pairo-Castineira, and Abdelkader Essafi. 2020. "Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling" Cancers 12, no. 10: 2823. https://doi.org/10.3390/cancers12102823

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