thesis published Claudia Igler author 46613666-F248-11E8-B48F-1D18A9856A870000-0001-7777-546X Calin C Guet supervisor CaGu department Design principles underlying genetic switch architecture project 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. https://research-explorer.ista.ac.at/download/6371/6373/IglerClaudia_OntheNatureofGeneRegulatoryDesign.pdf application/pdf2020-05-02no https://research-explorer.ista.ac.at/download/6371/6374/IglerClaudia_OntheNatureofGeneRegulatoryDesign.docx application/vnd.openxmlformats-officedocument.wordprocessingml.document Institute of Science and Technology Austria2019 eng gene regulationbiophysicstranscription factor bindingbacteria 2663-337X10.15479/AT:ISTA:6371 152 https://research-explorer.ista.ac.at/record/67 https://research-explorer.ista.ac.at/record/5585 Igler, C. (2019). <i>On the nature of gene regulatory design - The biophysics of transcription factor binding shapes gene regulation</i>. Institute of Science and Technology Austria. <a href="https://doi.org/10.15479/AT:ISTA:6371">https://doi.org/10.15479/AT:ISTA:6371</a> Igler, Claudia. <i>On the Nature of Gene Regulatory Design - The Biophysics of Transcription Factor Binding Shapes Gene Regulation</i>. Institute of Science and Technology Austria, 2019, doi:<a href="https://doi.org/10.15479/AT:ISTA:6371">10.15479/AT:ISTA:6371</a>. C. Igler, On the Nature of Gene Regulatory Design - The Biophysics of Transcription Factor Binding Shapes Gene Regulation, Institute of Science and Technology Austria, 2019. 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> C. Igler, “On the nature of gene regulatory design - The biophysics of transcription factor binding shapes gene regulation,” Institute of Science and Technology Austria, 2019. Igler, Claudia. “On the Nature of Gene Regulatory Design - The Biophysics of Transcription Factor Binding Shapes Gene Regulation.” Institute of Science and Technology Austria, 2019. <a href="https://doi.org/10.15479/AT:ISTA:6371">https://doi.org/10.15479/AT:ISTA:6371</a>. Igler C. 2019. On the nature of gene regulatory design - The biophysics of transcription factor binding shapes gene regulation. Institute of Science and Technology Austria. 63712019-05-03T11:55:51Z2026-04-08T13:56:27Z