Transcription factor interactions explain the context-dependent activity of CRX binding sites.
The effects of transcription factor binding sites (TFBSs) on the activity of a cis-regulatory element (CRE) depend on the local sequence context. In rod photoreceptors, binding sites for the transcription factor (TF) Cone-rod homeobox (CRX) occur in both enhancers and silencers, but the sequence con...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2024-01-01
|
| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1011802&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850202873491619840 |
|---|---|
| author | Kaiser J Loell Ryan Z Friedman Connie A Myers Joseph C Corbo Barak A Cohen Michael A White |
| author_facet | Kaiser J Loell Ryan Z Friedman Connie A Myers Joseph C Corbo Barak A Cohen Michael A White |
| author_sort | Kaiser J Loell |
| collection | DOAJ |
| description | The effects of transcription factor binding sites (TFBSs) on the activity of a cis-regulatory element (CRE) depend on the local sequence context. In rod photoreceptors, binding sites for the transcription factor (TF) Cone-rod homeobox (CRX) occur in both enhancers and silencers, but the sequence context that determines whether CRX binding sites contribute to activation or repression of transcription is not understood. To investigate the context-dependent activity of CRX sites, we fit neural network-based models to the activities of synthetic CREs composed of photoreceptor TFBSs. The models revealed that CRX binding sites consistently make positive, independent contributions to CRE activity, while negative homotypic interactions between sites cause CREs composed of multiple CRX sites to function as silencers. The effects of negative homotypic interactions can be overcome by the presence of other TFBSs that either interact cooperatively with CRX sites or make independent positive contributions to activity. The context-dependent activity of CRX sites is thus determined by the balance between positive heterotypic interactions, independent contributions of TFBSs, and negative homotypic interactions. Our findings explain observed patterns of activity among genomic CRX-bound enhancers and silencers, and suggest that enhancers may require diverse TFBSs to overcome negative homotypic interactions between TFBSs. |
| format | Article |
| id | doaj-art-23ab48da7da341368da6f3e8978fd5ec |
| institution | OA Journals |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-23ab48da7da341368da6f3e8978fd5ec2025-08-20T02:11:38ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582024-01-01201e101180210.1371/journal.pcbi.1011802Transcription factor interactions explain the context-dependent activity of CRX binding sites.Kaiser J LoellRyan Z FriedmanConnie A MyersJoseph C CorboBarak A CohenMichael A WhiteThe effects of transcription factor binding sites (TFBSs) on the activity of a cis-regulatory element (CRE) depend on the local sequence context. In rod photoreceptors, binding sites for the transcription factor (TF) Cone-rod homeobox (CRX) occur in both enhancers and silencers, but the sequence context that determines whether CRX binding sites contribute to activation or repression of transcription is not understood. To investigate the context-dependent activity of CRX sites, we fit neural network-based models to the activities of synthetic CREs composed of photoreceptor TFBSs. The models revealed that CRX binding sites consistently make positive, independent contributions to CRE activity, while negative homotypic interactions between sites cause CREs composed of multiple CRX sites to function as silencers. The effects of negative homotypic interactions can be overcome by the presence of other TFBSs that either interact cooperatively with CRX sites or make independent positive contributions to activity. The context-dependent activity of CRX sites is thus determined by the balance between positive heterotypic interactions, independent contributions of TFBSs, and negative homotypic interactions. Our findings explain observed patterns of activity among genomic CRX-bound enhancers and silencers, and suggest that enhancers may require diverse TFBSs to overcome negative homotypic interactions between TFBSs.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1011802&type=printable |
| spellingShingle | Kaiser J Loell Ryan Z Friedman Connie A Myers Joseph C Corbo Barak A Cohen Michael A White Transcription factor interactions explain the context-dependent activity of CRX binding sites. PLoS Computational Biology |
| title | Transcription factor interactions explain the context-dependent activity of CRX binding sites. |
| title_full | Transcription factor interactions explain the context-dependent activity of CRX binding sites. |
| title_fullStr | Transcription factor interactions explain the context-dependent activity of CRX binding sites. |
| title_full_unstemmed | Transcription factor interactions explain the context-dependent activity of CRX binding sites. |
| title_short | Transcription factor interactions explain the context-dependent activity of CRX binding sites. |
| title_sort | transcription factor interactions explain the context dependent activity of crx binding sites |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1011802&type=printable |
| work_keys_str_mv | AT kaiserjloell transcriptionfactorinteractionsexplainthecontextdependentactivityofcrxbindingsites AT ryanzfriedman transcriptionfactorinteractionsexplainthecontextdependentactivityofcrxbindingsites AT connieamyers transcriptionfactorinteractionsexplainthecontextdependentactivityofcrxbindingsites AT josephccorbo transcriptionfactorinteractionsexplainthecontextdependentactivityofcrxbindingsites AT barakacohen transcriptionfactorinteractionsexplainthecontextdependentactivityofcrxbindingsites AT michaelawhite transcriptionfactorinteractionsexplainthecontextdependentactivityofcrxbindingsites |