On the nature of gene regulatory design - The biophysics of transcription factor binding shapes gene regulation

By: Material type: TextTextPublication details: IST Austria 2019Online resources:
Contents:
Abstract
Acknowledgements
About the Author
List of Publications Appearing in Thesis
List of Figures
List of Tables
List of Symbols/Abbreviations
1 Introduction
2 Evolutionary potential of transcription factors for gene regulatory rewiring
3 Global crosstalk between transcription factors can enhance specificity
4 The evolution of phage immunity regions
5 Non-specific TF binding inhibits cellular growth
6 TF interference produces transient promoter memory in response to signal timing
7 Conclusion
References
Summary: Decades of studies have revealed the mechanisms of gene regulation in molecular detail. We make use of such well-described regulatory systems to explore how the molecular mechanisms of protein-protein and protein-DNA interactions shape the dynamics and evolution of gene regulation. i) We uncover how the biophysics of protein-DNA binding determines the potential of regulatory networks to evolve and adapt, which can be captured using a simple mathematical model. ii) The evolution of regulatory connections can lead to a significant amount of crosstalk between binding proteins. We explore the effect of crosstalk on gene expression from a target promoter, which seems to be modulated through binding competition at non-specific DNA sites. iii) We investigate how the very same biophysical characteristics as in i) can generate significant fitness costs for cells through global crosstalk, meaning non-specific DNA binding across the genomic background. iv) Binding competition between proteins at a target promoter is a prevailing regulatory feature due to the prevalence of co-regulation at bacterial promoters. However, the dynamics of these systems are not always straightforward to determine even if the molecular mechanisms of regulation are known. A detailed model of the biophysical interactions reveals that interference between the regulatory proteins can constitute a new, generic form of system memory that records the history of the input signals at the promoter. We demonstrate how the biophysics of protein-DNA binding can be harnessed to investigate the principles that shape and ultimately limit cellular gene regulation. These results provide a basis for studies of higher-level functionality, which arises from the underlying regulation.
List(s) this item appears in: ISTA Thesis

Thesis

Abstract

Acknowledgements

About the Author

List of Publications Appearing in Thesis

List of Figures

List of Tables

List of Symbols/Abbreviations

1 Introduction

2 Evolutionary potential of transcription factors for gene regulatory rewiring

3 Global crosstalk between transcription factors can enhance specificity

4 The evolution of phage immunity regions

5 Non-specific TF binding inhibits cellular growth

6 TF interference produces transient promoter memory in response to signal timing

7 Conclusion

References

Decades of studies have revealed the mechanisms of gene regulation in molecular detail. We make use of such well-described regulatory systems to explore how the molecular mechanisms of protein-protein and protein-DNA interactions shape the dynamics and evolution of gene regulation. i) We uncover how the biophysics of protein-DNA binding determines the potential of regulatory networks to evolve and adapt, which can be captured using a simple mathematical model. ii) The evolution of regulatory connections can lead to a significant amount of crosstalk between binding proteins. We explore the effect of crosstalk on gene expression from a target promoter, which seems to be modulated through binding competition at non-specific DNA sites. iii) We investigate how the very same biophysical characteristics as in i) can generate significant fitness costs for cells through global crosstalk, meaning non-specific DNA binding across the genomic background. iv) Binding competition between proteins at a target promoter is a prevailing regulatory feature due to the prevalence of co-regulation at bacterial promoters. However, the dynamics of these systems are not always straightforward to determine even if the molecular mechanisms of regulation are known. A detailed model of the biophysical interactions reveals that interference between the regulatory proteins can constitute a new, generic form of system memory that records the history of the input signals at the promoter. We demonstrate how the biophysics of protein-DNA binding can be harnessed to investigate the principles that shape and ultimately limit cellular gene regulation. These results provide a basis for studies of higher-level functionality, which arises from the underlying regulation.

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