[{"abstract":[{"text":"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. \r\n\r\ni) 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. \r\nii) 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. \r\niii) 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. \r\niv) 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. \r\n\r\nWe 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.   \r\n","lang":"eng"}],"degree_awarded":"PhD","doi":"10.15479/AT:ISTA:6371","day":"03","date_updated":"2024-02-21T13:45:52Z","citation":{"chicago":"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>.","ieee":"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.","apa":"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>","ama":"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>","ista":"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.","mla":"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>.","short":"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."},"year":"2019","ddc":["576","579"],"alternative_title":["ISTA Thesis"],"title":"On the nature of gene regulatory design - The biophysics of transcription factor binding shapes gene regulation","publication_status":"published","date_created":"2019-05-03T11:55:51Z","article_processing_charge":"No","department":[{"_id":"CaGu"}],"author":[{"full_name":"Igler, Claudia","first_name":"Claudia","last_name":"Igler","id":"46613666-F248-11E8-B48F-1D18A9856A87"}],"_id":"6371","publisher":"Institute of Science and Technology Austria","file_date_updated":"2021-02-11T11:17:13Z","page":"152","supervisor":[{"id":"47F8433E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6220-2052","full_name":"Guet, Calin C","first_name":"Calin C","last_name":"Guet"}],"oa":1,"publication_identifier":{"issn":["2663-337X"]},"date_published":"2019-05-03T00:00:00Z","type":"dissertation","status":"public","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","related_material":{"record":[{"id":"67","relation":"part_of_dissertation","status":"public"},{"relation":"popular_science","id":"5585","status":"public"}]},"file":[{"relation":"main_file","access_level":"open_access","creator":"cigler","file_id":"6373","checksum":"c0085d47c58c9cbcab1b0a783480f6da","file_size":12597663,"date_created":"2019-05-03T11:54:52Z","embargo":"2020-05-02","content_type":"application/pdf","file_name":"IglerClaudia_OntheNatureofGeneRegulatoryDesign.pdf","date_updated":"2021-02-11T11:17:13Z"},{"date_updated":"2020-07-14T12:47:28Z","file_name":"IglerClaudia_OntheNatureofGeneRegulatoryDesign.docx","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","date_created":"2019-05-03T11:54:54Z","embargo_to":"open_access","file_size":34644426,"checksum":"2eac954de1c8bbf7e6fb35ed0221ae8c","file_id":"6374","creator":"cigler","relation":"source_file","access_level":"closed"}],"month":"05","oa_version":"Published Version","project":[{"name":"Design principles underlying genetic switch architecture (DOC Fellowship)","grant_number":"24573","_id":"251EE76E-B435-11E9-9278-68D0E5697425"}],"has_accepted_license":"1","language":[{"iso":"eng"}],"keyword":["gene regulation","biophysics","transcription factor binding","bacteria"]},{"file":[{"relation":"main_file","access_level":"open_access","creator":"system","file_id":"5616","checksum":"ee697f2b1ade4dc14d6ac0334dd832ab","file_size":296722548,"date_created":"2018-12-12T13:02:58Z","file_name":"IST-2016-45-v1+1_PaperCode.zip","content_type":"application/zip","date_updated":"2020-07-14T12:47:02Z"}],"status":"public","related_material":{"record":[{"id":"8431","relation":"used_in_publication","status":"deleted"},{"status":"public","relation":"research_paper","id":"1029"}]},"ddc":["571"],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","citation":{"mla":"Lukacisin, Martin, et al. <i>MATLAB Analysis Code for “Sequence-Specific Thermodynamic Properties of Nucleic Acids Influence Both Transcriptional Pausing and Backtracking in Yeast.”</i> Institute of Science and Technology Austria, 2016, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:45\">10.15479/AT:ISTA:45</a>.","short":"M. Lukacisin, M. Landon, R. Jajoo, (2016).","ista":"Lukacisin M, Landon M, Jajoo R. 2016. MATLAB analysis code for ‘Sequence-Specific Thermodynamic Properties of Nucleic Acids Influence Both Transcriptional Pausing and Backtracking in Yeast’, Institute of Science and Technology Austria, <a href=\"https://doi.org/10.15479/AT:ISTA:45\">10.15479/AT:ISTA:45</a>.","ama":"Lukacisin M, Landon M, Jajoo R. MATLAB analysis code for “Sequence-Specific Thermodynamic Properties of Nucleic Acids Influence Both Transcriptional Pausing and Backtracking in Yeast.” 2016. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:45\">10.15479/AT:ISTA:45</a>","apa":"Lukacisin, M., Landon, M., &#38; Jajoo, R. (2016). MATLAB analysis code for “Sequence-Specific Thermodynamic Properties of Nucleic Acids Influence Both Transcriptional Pausing and Backtracking in Yeast.” Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:45\">https://doi.org/10.15479/AT:ISTA:45</a>","chicago":"Lukacisin, Martin, Matthieu Landon, and Rishi Jajoo. “MATLAB Analysis Code for ‘Sequence-Specific Thermodynamic Properties of Nucleic Acids Influence Both Transcriptional Pausing and Backtracking in Yeast.’” Institute of Science and Technology Austria, 2016. <a href=\"https://doi.org/10.15479/AT:ISTA:45\">https://doi.org/10.15479/AT:ISTA:45</a>.","ieee":"M. Lukacisin, M. Landon, and R. Jajoo, “MATLAB analysis code for ‘Sequence-Specific Thermodynamic Properties of Nucleic Acids Influence Both Transcriptional Pausing and Backtracking in Yeast.’” Institute of Science and Technology Austria, 2016."},"year":"2016","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-sa/4.0/legalcode","short":"CC BY-SA (4.0)","name":"Creative Commons Attribution-ShareAlike 4.0 International Public License (CC BY-SA 4.0)","image":"/images/cc_by_sa.png"},"date_updated":"2024-02-21T13:51:53Z","type":"research_data","date_published":"2016-08-25T00:00:00Z","day":"25","doi":"10.15479/AT:ISTA:45","oa":1,"abstract":[{"text":"MATLAB code and processed datasets available for reproducing the results in: \r\nLukačišin, M.*, Landon, M.*, Jajoo, R*. (2016) Sequence-Specific Thermodynamic Properties of Nucleic Acids Influence Both Transcriptional Pausing and Backtracking in Yeast.\r\n*equal contributions","lang":"eng"}],"keyword":["transcription","pausing","backtracking","polymerase","RNA","NET-seq","nucleosome","basepairing"],"file_date_updated":"2020-07-14T12:47:02Z","publisher":"Institute of Science and Technology Austria","has_accepted_license":"1","license":"https://creativecommons.org/licenses/by-sa/4.0/","_id":"5556","datarep_id":"45","author":[{"id":"298FFE8C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6549-4177","full_name":"Lukacisin, Martin","first_name":"Martin","last_name":"Lukacisin"},{"full_name":"Landon, Matthieu","last_name":"Landon","first_name":"Matthieu"},{"full_name":"Jajoo, Rishi","first_name":"Rishi","last_name":"Jajoo"}],"date_created":"2018-12-12T12:31:31Z","article_processing_charge":"No","department":[{"_id":"ToBo"}],"oa_version":"Published Version","title":"MATLAB analysis code for 'Sequence-Specific Thermodynamic Properties of Nucleic Acids Influence Both Transcriptional Pausing and Backtracking in Yeast'","month":"08"},{"main_file_link":[{"open_access":"1","url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1207552/"}],"user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","status":"public","type":"journal_article","date_published":"1996-10-01T00:00:00Z","publication_identifier":{"issn":["00166731"]},"oa":1,"keyword":["amino acid sequence","article","caenorhabditis elegans","evolution","genetic variability","nonhuman","priority journal","sex determination","Amino Acid Sequence","Animals","Animals","Genetically Modified","Base Sequence","Caenorhabditis","Caenorhabditis elegans","Caenorhabditis elegans Proteins","DNA","Helminth","DNA-Binding Proteins","Evolution","Molecular","Female","Helminth Proteins","Membrane Proteins","Molecular Sequence Data","Mutagenesis","RNA","Messenger","Sequence Homology","Amino Acid","Sex Determination (Analysis)","Transcription Factors","Transgenes","Turner Syndrome","Animalia","Caenorhabditis","Caenorhabditis briggsae","Caenorhabditis elegans","Nematoda"],"language":[{"iso":"eng"}],"publication":"Genetics","oa_version":"Published Version","month":"10","volume":144,"extern":"1","citation":{"ama":"de Bono M, Hodgkin J. Evolution of sex determination in Caenorhabditis: Unusually high divergence of tra-1 and its functional consequences. <i>Genetics</i>. 1996;144(2):587-595.","apa":"de Bono, M., &#38; Hodgkin, J. (1996). Evolution of sex determination in Caenorhabditis: Unusually high divergence of tra-1 and its functional consequences. <i>Genetics</i>. Genetics Society of America.","ieee":"M. de Bono and J. Hodgkin, “Evolution of sex determination in Caenorhabditis: Unusually high divergence of tra-1 and its functional consequences,” <i>Genetics</i>, vol. 144, no. 2. Genetics Society of America, pp. 587–595, 1996.","chicago":"Bono, Mario de, and J. Hodgkin. “Evolution of Sex Determination in Caenorhabditis: Unusually High Divergence of Tra-1 and Its Functional Consequences.” <i>Genetics</i>. Genetics Society of America, 1996.","short":"M. de Bono, J. Hodgkin, Genetics 144 (1996) 587–595.","mla":"de Bono, Mario, and J. Hodgkin. “Evolution of Sex Determination in Caenorhabditis: Unusually High Divergence of Tra-1 and Its Functional Consequences.” <i>Genetics</i>, vol. 144, no. 2, Genetics Society of America, 1996, pp. 587–95.","ista":"de Bono M, Hodgkin J. 1996. Evolution of sex determination in Caenorhabditis: Unusually high divergence of tra-1 and its functional consequences. Genetics. 144(2), 587–595."},"year":"1996","date_updated":"2021-01-12T08:06:28Z","external_id":{"pmid":["8889522"]},"day":"01","abstract":[{"text":"The tra-1 gene is a terminal regulator of somatic sex in Caenorhabditis elegans: high tra-1 activity elicits female development, low tra-1 activity elicits male development. To investigate the function and evolution of tra- 1, we examined the tra-1 gene from the closely related nematode C. briggsae. Ce-tra-1 and Cb-tra-1 are unusually divergent. Each gene generates two transcripts, but only one of these is present in both species. This common transcript encodes TRA-1A, which shows only 44% amino acid identity between the species, a figure much lower than that for previously compared genes. A Cb-tra-1 transgene rescues many tissues of tra-1(null) mutants of C. elegans but not the somatic gonad or germ line. This transgene also causes nongonadal feminization of XO animals, indicating incorrect sexual regulation. Alignment of Ce-TRA-1A and Cb-TRA-1A defined several conserved regions likely to be important for tra-1 function. The phenotype differences between Ce-tra- 1(null) mutants rescued by Cb-tra-1 transgenes and wild-type C. elegans indicate significant divergence of regulatory regions. These molecular and functional studies suggest that evolution of sex determination in nematodes is rapid and genetically complex.","lang":"eng"}],"quality_controlled":"1","page":"587-595","publisher":"Genetics Society of America","_id":"6161","pmid":1,"issue":"2","author":[{"orcid":"0000-0001-8347-0443","full_name":"de Bono, Mario","first_name":"Mario","last_name":"de Bono","id":"4E3FF80E-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Hodgkin, J.","last_name":"Hodgkin","first_name":"J."}],"date_created":"2019-03-21T11:50:37Z","publication_status":"published","intvolume":"       144","title":"Evolution of sex determination in Caenorhabditis: Unusually high divergence of tra-1 and its functional consequences"}]