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Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling

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...

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Autores principales: Overton, Ian M., Sims, Andrew H., Owen, Jeremy A., Heale, Bret S. E., Ford, Matthew J., Lubbock, Alexander L. R., Pairo-Castineira, Erola, Essafi, Abdelkader
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652213/
https://www.ncbi.nlm.nih.gov/pubmed/33007944
http://dx.doi.org/10.3390/cancers12102823
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author Overton, Ian M.
Sims, Andrew H.
Owen, Jeremy A.
Heale, Bret S. E.
Ford, Matthew J.
Lubbock, Alexander L. R.
Pairo-Castineira, Erola
Essafi, Abdelkader
author_facet Overton, Ian M.
Sims, Andrew H.
Owen, Jeremy A.
Heale, Bret S. E.
Ford, Matthew J.
Lubbock, Alexander L. R.
Pairo-Castineira, Erola
Essafi, Abdelkader
author_sort Overton, Ian M.
collection PubMed
description 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.
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spelling pubmed-76522132020-11-10 Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling Overton, Ian M. Sims, Andrew H. Owen, Jeremy A. Heale, Bret S. E. Ford, Matthew J. Lubbock, Alexander L. R. Pairo-Castineira, Erola Essafi, Abdelkader Cancers (Basel) Article 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. MDPI 2020-09-30 /pmc/articles/PMC7652213/ /pubmed/33007944 http://dx.doi.org/10.3390/cancers12102823 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Overton, Ian M.
Sims, Andrew H.
Owen, Jeremy A.
Heale, Bret S. E.
Ford, Matthew J.
Lubbock, Alexander L. R.
Pairo-Castineira, Erola
Essafi, Abdelkader
Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling
title Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling
title_full Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling
title_fullStr Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling
title_full_unstemmed Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling
title_short Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling
title_sort functional transcription factor target networks illuminate control of epithelial remodelling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652213/
https://www.ncbi.nlm.nih.gov/pubmed/33007944
http://dx.doi.org/10.3390/cancers12102823
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