On the nature of gene regulatory design - The biophysics of transcription factor binding shapes gene regulation
Igler, Claudia
On the nature of gene regulatory design - The biophysics of transcription factor binding shapes gene regulation - IST Austria 2019
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.
On the nature of gene regulatory design - The biophysics of transcription factor binding shapes gene regulation - IST Austria 2019
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.