On the nature of gene regulatory design - The biophysics of transcription factor binding shapes gene regulation ISTA Thesis Igler, Claudia ; https://orcid.org/0000-0001-7777-546X gene regulation biophysics transcription factor binding bacteria ddc:576 ddc:579 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. Institute of Science and Technology Austria 2019 info:eu-repo/semantics/doctoralThesis doc-type:doctoralThesis text http://purl.org/coar/resource_type/c_db06 https://research-explorer.ista.ac.at/record/6371 https://research-explorer.ista.ac.at/download/6371/6373 Igler C. On the nature of gene regulatory design - The biophysics of transcription factor binding shapes gene regulation. 2019. doi:<a href="https://doi.org/10.15479/AT:ISTA:6371">10.15479/AT:ISTA:6371</a> eng info:eu-repo/semantics/altIdentifier/doi/10.15479/AT:ISTA:6371 info:eu-repo/semantics/altIdentifier/issn/2663-337X info:eu-repo/semantics/openAccess