PT  - JOURNAL ARTICLE
AU  - Ian M. Overton
AU  - Andrew H. Sims
AU  - Jeremy A. Owen
AU  - Bret S. E. Heale
AU  - Matthew J. Ford
AU  - Alexander L. R. Lubbock
AU  - Erola Pairo-Castineira
AU  - Abdelkader Essafi
TI  - Functionally Coherent Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling
AID  - 10.1101/455709
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 455709
4099  - http://biorxiv.org/content/early/2019/03/15/455709.short
4100  - http://biorxiv.org/content/early/2019/03/15/455709.full
AB  - 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.