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Transcription factor interactions explain the context-dependent activity of CRX binding sites
Kaiser J Loell1,2, Ryan Z Friedman1,2, Connie A Myers3
1Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States of America.
Plos Computational Biology
|January 16, 2024
Summary
Transcription factor binding sites (TFBSs) in rod photoreceptors exhibit context-dependent activity. Negative interactions between CRX sites can be overcome by other TFBSs, explaining enhancer and silencer function.
Area of Science:
- Molecular Biology
- Genetics
- Computational Biology
Background:
- Transcription factor binding sites (TFBSs) influence cis-regulatory element (CRE) activity based on local sequence context.
- The specific sequence context determining the function of Cone-rod homeobox (CRX) TFBSs in rod photoreceptors (activation vs. repression) remains unclear.
Purpose of the Study:
- To investigate the context-dependent activity of CRX binding sites within CREs.
- To elucidate the mechanisms underlying CRX site function in enhancers and silencers.
Main Methods:
- Utilized neural network-based models to analyze the activity of synthetic CREs.
- Composed synthetic CREs using photoreceptor TFBSs to systematically study interactions.
Main Results:
- CRX binding sites contribute positively and independently to CRE activity.
- Negative homotypic interactions between multiple CRX sites lead to silencer function.
- Positive heterotypic interactions or independent contributions from other TFBSs can override negative homotypic interactions.
Conclusions:
- The activity of CRX sites is determined by a balance of positive heterotypic interactions, independent TFBS contributions, and negative homotypic interactions.
- Genomic patterns of CRX-bound enhancers and silencers can be explained by these interaction dynamics.
- Enhancers may necessitate diverse TFBSs to counteract negative homotypic interactions.
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