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...
| Main Authors: | , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Published: |
Multidisciplinary Digital Publishing Institute
2021
|
| Online Access: | https://hdl.handle.net/1721.1/131303 |
| _version_ | 1826216102447808512 |
|---|---|
| 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 |
| author2 | Massachusetts Institute of Technology. Department of Physics |
| author_facet | Massachusetts Institute of Technology. Department of Physics 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 | MIT |
| 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 role<i>s</i> were validated using a tractable cell model, supporting our approach. |
| first_indexed | 2024-09-23T16:42:20Z |
| format | Article |
| id | mit-1721.1/131303 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T16:42:20Z |
| publishDate | 2021 |
| publisher | Multidisciplinary Digital Publishing Institute |
| record_format | dspace |
| spelling | mit-1721.1/1313032023-01-20T21:21:13Z 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 Massachusetts Institute of Technology. Department of Physics 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 role<i>s</i> were validated using a tractable cell model, supporting our approach. 2021-09-20T14:16:06Z 2021-09-20T14:16:06Z 2020-09-30 2020-10-13T13:24:25Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/131303 Cancers 12 (10): 2823 (2020) PUBLISHER_CC http://dx.doi.org/10.3390/cancers12102823 Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ application/pdf Multidisciplinary Digital Publishing Institute Multidisciplinary Digital Publishing Institute |
| spellingShingle | 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 |
| url | https://hdl.handle.net/1721.1/131303 |
| work_keys_str_mv | AT overtonianm functionaltranscriptionfactortargetnetworksilluminatecontrolofepithelialremodelling AT simsandrewh functionaltranscriptionfactortargetnetworksilluminatecontrolofepithelialremodelling AT owenjeremya functionaltranscriptionfactortargetnetworksilluminatecontrolofepithelialremodelling AT healebretse functionaltranscriptionfactortargetnetworksilluminatecontrolofepithelialremodelling AT fordmatthewj functionaltranscriptionfactortargetnetworksilluminatecontrolofepithelialremodelling AT lubbockalexanderlr functionaltranscriptionfactortargetnetworksilluminatecontrolofepithelialremodelling AT pairocastineiraerola functionaltranscriptionfactortargetnetworksilluminatecontrolofepithelialremodelling AT essafiabdelkader functionaltranscriptionfactortargetnetworksilluminatecontrolofepithelialremodelling |