[{"acknowledgement":"For the duration of his PhD, Rok was a recipient of a DOC fellowship of the Austrian Academy of Sciences.","ddc":["530","570"],"date_updated":"2023-09-07T13:13:27Z","citation":{"ieee":"R. Grah, “Gene regulation across scales – how biophysical constraints shape evolution,” Institute of Science and Technology Austria, 2020.","chicago":"Grah, Rok. “Gene Regulation across Scales – How Biophysical Constraints Shape Evolution.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:8155\">https://doi.org/10.15479/AT:ISTA:8155</a>.","apa":"Grah, R. (2020). <i>Gene regulation across scales – how biophysical constraints shape evolution</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:8155\">https://doi.org/10.15479/AT:ISTA:8155</a>","ama":"Grah R. Gene regulation across scales – how biophysical constraints shape evolution. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8155\">10.15479/AT:ISTA:8155</a>","ista":"Grah R. 2020. Gene regulation across scales – how biophysical constraints shape evolution. Institute of Science and Technology Austria.","mla":"Grah, Rok. <i>Gene Regulation across Scales – How Biophysical Constraints Shape Evolution</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8155\">10.15479/AT:ISTA:8155</a>.","short":"R. Grah, Gene Regulation across Scales – How Biophysical Constraints Shape Evolution, Institute of Science and Technology Austria, 2020."},"year":"2020","doi":"10.15479/AT:ISTA:8155","degree_awarded":"PhD","day":"24","abstract":[{"text":"In the thesis we focus on the interplay of the biophysics and evolution of gene regulation. We start by addressing how the type of prokaryotic gene regulation – activation and repression – affects spurious binding to DNA, also known as\r\ntranscriptional crosstalk. We propose that regulatory interference caused by excess regulatory proteins in the dense cellular medium – global crosstalk – could be a factor in determining which type of gene regulatory network is evolutionarily preferred. Next,we use a normative approach in eukaryotic gene regulation to describe minimal\r\nnon-equilibrium enhancer models that optimize so-called regulatory phenotypes. We find a class of models that differ from standard thermodynamic equilibrium models by a single parameter that notably increases the regulatory performance. Next chapter addresses the question of genotype-phenotype-fitness maps of higher dimensional phenotypes. We show that our biophysically realistic approach allows us to understand how the mechanisms of promoter function constrain genotypephenotype maps, and how they affect the evolutionary trajectories of promoters.\r\nIn the last chapter we ask whether the intrinsic instability of gene duplication and amplification provides a generic alternative to canonical gene regulation. Using mathematical modeling, we show that amplifications can tune gene expression in many environments, including those where transcription factor-based schemes are\r\nhard to evolve or maintain. ","lang":"eng"}],"page":"310","file_date_updated":"2020-07-30T13:04:55Z","publisher":"Institute of Science and Technology Austria","_id":"8155","author":[{"full_name":"Grah, Rok","orcid":"0000-0003-2539-3560","last_name":"Grah","first_name":"Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87"}],"publication_status":"published","date_created":"2020-07-23T09:51:28Z","article_processing_charge":"No","department":[{"_id":"CaGu"},{"_id":"GaTk"}],"alternative_title":["ISTA Thesis"],"title":"Gene regulation across scales – how biophysical constraints shape evolution","file":[{"file_size":16638998,"date_created":"2020-07-27T12:00:07Z","file_name":"Thesis_RokGrah_200727_convertedNew.pdf","content_type":"application/pdf","date_updated":"2020-07-27T12:00:07Z","access_level":"open_access","relation":"main_file","success":1,"creator":"rgrah","file_id":"8176"},{"file_size":347459978,"date_created":"2020-07-27T12:02:23Z","content_type":"application/zip","file_name":"Thesis_new.zip","date_updated":"2020-07-30T13:04:55Z","relation":"main_file","access_level":"closed","creator":"rgrah","file_id":"8177"}],"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","related_material":{"record":[{"status":"public","relation":"part_of_dissertation","id":"7675"},{"relation":"part_of_dissertation","id":"7569","status":"public"},{"relation":"part_of_dissertation","id":"7652","status":"public"}]},"status":"public","date_published":"2020-07-24T00:00:00Z","type":"dissertation","publication_identifier":{"issn":["2663-337X"]},"supervisor":[{"id":"47F8433E-F248-11E8-B48F-1D18A9856A87","last_name":"Guet","first_name":"Calin C","full_name":"Guet, Calin C","orcid":"0000-0001-6220-2052"},{"id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-6699-1455","full_name":"Tkačik, Gašper","first_name":"Gašper","last_name":"Tkačik"}],"oa":1,"language":[{"iso":"eng"}],"has_accepted_license":"1","oa_version":"Published Version","project":[{"name":"Biophysically realistic genotype-phenotype maps for regulatory networks","_id":"267C84F4-B435-11E9-9278-68D0E5697425"}],"month":"07"},{"status":"public","related_material":{"link":[{"url":"https://ist.ac.at/en/news/new-compact-model-for-gene-regulation-in-higher-organisms/","relation":"press_release","description":"News on IST Homepage"}]},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","file":[{"success":1,"access_level":"open_access","relation":"main_file","creator":"dernst","file_id":"9004","file_size":1199247,"checksum":"69039cd402a571983aa6cb4815ffa863","date_created":"2021-01-11T08:37:31Z","file_name":"2020_PNAS_Grah.pdf","content_type":"application/pdf","date_updated":"2021-01-11T08:37:31Z"}],"date_published":"2020-12-15T00:00:00Z","type":"journal_article","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","short":"CC BY-NC-ND (4.0)","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","image":"/images/cc_by_nc_nd.png"},"oa":1,"publication_identifier":{"eissn":["10916490"],"issn":["00278424"]},"language":[{"iso":"eng"}],"publication":"PNAS","has_accepted_license":"1","month":"12","oa_version":"Published Version","project":[{"grant_number":"RGP0034/2018","name":"Can evolution minimize spurious signaling crosstalk to reach optimal performance?","_id":"2665AAFE-B435-11E9-9278-68D0E5697425"},{"name":"Biophysically realistic genotype-phenotype maps for regulatory networks","_id":"267C84F4-B435-11E9-9278-68D0E5697425"}],"ddc":["570"],"volume":117,"acknowledgement":"G.T. was supported by Human Frontiers Science Program Grant RGP0034/2018. R.G. was supported by the Austrian Academy of Sciences DOC Fellowship. R.G. thanks S. Avvakumov for helpful discussions.","isi":1,"external_id":{"pmid":["33268497"],"isi":["000600608300015"]},"date_updated":"2023-08-24T11:10:22Z","year":"2020","citation":{"ista":"Grah R, Zoller B, Tkačik G. 2020. Nonequilibrium models of optimal enhancer function. PNAS. 117(50), 31614–31622.","mla":"Grah, Rok, et al. “Nonequilibrium Models of Optimal Enhancer Function.” <i>PNAS</i>, vol. 117, no. 50, National Academy of Sciences, 2020, pp. 31614–22, doi:<a href=\"https://doi.org/10.1073/pnas.2006731117\">10.1073/pnas.2006731117</a>.","short":"R. Grah, B. Zoller, G. Tkačik, PNAS 117 (2020) 31614–31622.","chicago":"Grah, Rok, Benjamin Zoller, and Gašper Tkačik. “Nonequilibrium Models of Optimal Enhancer Function.” <i>PNAS</i>. National Academy of Sciences, 2020. <a href=\"https://doi.org/10.1073/pnas.2006731117\">https://doi.org/10.1073/pnas.2006731117</a>.","ieee":"R. Grah, B. Zoller, and G. Tkačik, “Nonequilibrium models of optimal enhancer function,” <i>PNAS</i>, vol. 117, no. 50. National Academy of Sciences, pp. 31614–31622, 2020.","ama":"Grah R, Zoller B, Tkačik G. Nonequilibrium models of optimal enhancer function. <i>PNAS</i>. 2020;117(50):31614-31622. doi:<a href=\"https://doi.org/10.1073/pnas.2006731117\">10.1073/pnas.2006731117</a>","apa":"Grah, R., Zoller, B., &#38; Tkačik, G. (2020). Nonequilibrium models of optimal enhancer function. <i>PNAS</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.2006731117\">https://doi.org/10.1073/pnas.2006731117</a>"},"abstract":[{"text":"In prokaryotes, thermodynamic models of gene regulation provide a highly quantitative mapping from promoter sequences to gene-expression levels that is compatible with in vivo and in vitro biophysical measurements. Such concordance has not been achieved for models of enhancer function in eukaryotes. In equilibrium models, it is difficult to reconcile the reported short transcription factor (TF) residence times on the DNA with the high specificity of regulation. In nonequilibrium models, progress is difficult due to an explosion in the number of parameters. Here, we navigate this complexity by looking for minimal nonequilibrium enhancer models that yield desired regulatory phenotypes: low TF residence time, high specificity, and tunable cooperativity. We find that a single extra parameter, interpretable as the “linking rate,” by which bound TFs interact with Mediator components, enables our models to escape equilibrium bounds and access optimal regulatory phenotypes, while remaining consistent with the reported phenomenology and simple enough to be inferred from upcoming experiments. We further find that high specificity in nonequilibrium models is in a trade-off with gene-expression noise, predicting bursty dynamics—an experimentally observed hallmark of eukaryotic transcription. By drastically reducing the vast parameter space of nonequilibrium enhancer models to a much smaller subspace that optimally realizes biological function, we deliver a rich class of models that could be tractably inferred from data in the near future.","lang":"eng"}],"doi":"10.1073/pnas.2006731117","day":"15","file_date_updated":"2021-01-11T08:37:31Z","page":"31614-31622","quality_controlled":"1","article_type":"original","publisher":"National Academy of Sciences","author":[{"orcid":"0000-0003-2539-3560","full_name":"Grah, Rok","first_name":"Rok","last_name":"Grah","id":"483E70DE-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Zoller","first_name":"Benjamin","full_name":"Zoller, Benjamin"},{"first_name":"Gašper","last_name":"Tkačik","orcid":"0000-0002-6699-1455","full_name":"Tkačik, Gašper","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87"}],"issue":"50","_id":"9000","pmid":1,"scopus_import":"1","title":"Nonequilibrium models of optimal enhancer function","intvolume":"       117","publication_status":"published","date_created":"2021-01-10T23:01:17Z","department":[{"_id":"GaTk"}],"article_processing_charge":"No"},{"file_date_updated":"2020-10-09T09:56:01Z","page":"612-625","quality_controlled":"1","article_type":"original","publisher":"Springer Nature","author":[{"id":"3981F020-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6197-363X","full_name":"Tomanek, Isabella","first_name":"Isabella","last_name":"Tomanek"},{"orcid":"0000-0003-2539-3560","full_name":"Grah, Rok","first_name":"Rok","last_name":"Grah","id":"483E70DE-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Lagator, M.","first_name":"M.","last_name":"Lagator"},{"first_name":"A. M. C.","last_name":"Andersson","full_name":"Andersson, A. M. C."},{"id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87","first_name":"Jonathan P","last_name":"Bollback","orcid":"0000-0002-4624-4612","full_name":"Bollback, Jonathan P"},{"id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-6699-1455","full_name":"Tkačik, Gašper","first_name":"Gašper","last_name":"Tkačik"},{"first_name":"Calin C","last_name":"Guet","orcid":"0000-0001-6220-2052","full_name":"Guet, Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87"}],"issue":"4","_id":"7652","scopus_import":"1","title":"Gene amplification as a form of population-level gene expression regulation","intvolume":"         4","publication_status":"published","department":[{"_id":"GaTk"},{"_id":"CaGu"}],"article_processing_charge":"No","date_created":"2020-04-08T15:20:53Z","ddc":["570"],"acknowledgement":"We thank L. Hurst, N. Barton, M. Pleska, M. Steinrück, B. Kavcic and A. Staron for input on the manuscript, and To. Bergmiller and R. Chait for help with microfluidics experiments. I.T. is a recipient the OMV fellowship. R.G. is a recipient of a DOC (Doctoral Fellowship Programme of the Austrian Academy of Sciences) Fellowship of the Austrian Academy of Sciences.","volume":4,"isi":1,"external_id":{"isi":["000519008300005"]},"date_updated":"2024-03-25T23:30:20Z","citation":{"ieee":"I. Tomanek <i>et al.</i>, “Gene amplification as a form of population-level gene expression regulation,” <i>Nature Ecology &#38; Evolution</i>, vol. 4, no. 4. Springer Nature, pp. 612–625, 2020.","chicago":"Tomanek, Isabella, Rok Grah, M. Lagator, A. M. C. Andersson, Jonathan P Bollback, Gašper Tkačik, and Calin C Guet. “Gene Amplification as a Form of Population-Level Gene Expression Regulation.” <i>Nature Ecology &#38; Evolution</i>. Springer Nature, 2020. <a href=\"https://doi.org/10.1038/s41559-020-1132-7\">https://doi.org/10.1038/s41559-020-1132-7</a>.","apa":"Tomanek, I., Grah, R., Lagator, M., Andersson, A. M. C., Bollback, J. P., Tkačik, G., &#38; Guet, C. C. (2020). Gene amplification as a form of population-level gene expression regulation. <i>Nature Ecology &#38; Evolution</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41559-020-1132-7\">https://doi.org/10.1038/s41559-020-1132-7</a>","ama":"Tomanek I, Grah R, Lagator M, et al. Gene amplification as a form of population-level gene expression regulation. <i>Nature Ecology &#38; Evolution</i>. 2020;4(4):612-625. doi:<a href=\"https://doi.org/10.1038/s41559-020-1132-7\">10.1038/s41559-020-1132-7</a>","ista":"Tomanek I, Grah R, Lagator M, Andersson AMC, Bollback JP, Tkačik G, Guet CC. 2020. Gene amplification as a form of population-level gene expression regulation. Nature Ecology &#38; Evolution. 4(4), 612–625.","mla":"Tomanek, Isabella, et al. “Gene Amplification as a Form of Population-Level Gene Expression Regulation.” <i>Nature Ecology &#38; Evolution</i>, vol. 4, no. 4, Springer Nature, 2020, pp. 612–25, doi:<a href=\"https://doi.org/10.1038/s41559-020-1132-7\">10.1038/s41559-020-1132-7</a>.","short":"I. Tomanek, R. Grah, M. Lagator, A.M.C. Andersson, J.P. Bollback, G. Tkačik, C.C. Guet, Nature Ecology &#38; Evolution 4 (2020) 612–625."},"year":"2020","abstract":[{"text":"Organisms cope with change by taking advantage of transcriptional regulators. However, when faced with rare environments, the evolution of transcriptional regulators and their promoters may be too slow. Here, we investigate whether the intrinsic instability of gene duplication and amplification provides a generic alternative to canonical gene regulation. Using real-time monitoring of gene-copy-number mutations in Escherichia coli, we show that gene duplications and amplifications enable adaptation to fluctuating environments by rapidly generating copy-number and, therefore, expression-level polymorphisms. This amplification-mediated gene expression tuning (AMGET) occurs on timescales that are similar to canonical gene regulation and can respond to rapid environmental changes. Mathematical modelling shows that amplifications also tune gene expression in stochastic environments in which transcription-factor-based schemes are hard to evolve or maintain. The fleeting nature of gene amplifications gives rise to a generic population-level mechanism that relies on genetic heterogeneity to rapidly tune the expression of any gene, without leaving any genomic signature.","lang":"eng"}],"doi":"10.1038/s41559-020-1132-7","day":"01","language":[{"iso":"eng"}],"publication":"Nature Ecology & Evolution","has_accepted_license":"1","month":"04","oa_version":"Submitted Version","project":[{"_id":"267C84F4-B435-11E9-9278-68D0E5697425","name":"Biophysically realistic genotype-phenotype maps for regulatory networks"}],"status":"public","related_material":{"link":[{"url":"https://ist.ac.at/en/news/how-to-thrive-without-gene-regulation/","description":"News on IST Homepage","relation":"press_release"}],"record":[{"status":"public","id":"8155","relation":"dissertation_contains"},{"status":"public","relation":"research_data","id":"7383"},{"relation":"research_data","id":"7016","status":"public"},{"id":"8653","relation":"used_in_publication","status":"public"}]},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","file":[{"success":1,"relation":"main_file","access_level":"open_access","file_id":"8640","creator":"dernst","date_created":"2020-10-09T09:56:01Z","checksum":"ef3bbf42023e30b2c24a6278025d2040","file_size":745242,"date_updated":"2020-10-09T09:56:01Z","content_type":"application/pdf","file_name":"2020_NatureEcolEvo_Tomanek.pdf"}],"date_published":"2020-04-01T00:00:00Z","type":"journal_article","oa":1,"publication_identifier":{"issn":["2397-334X"]}},{"type":"preprint","date_published":"2020-04-09T00:00:00Z","citation":{"ama":"Grah R, Zoller B, Tkačik G. Normative models of enhancer function. <i>bioRxiv</i>. 2020. doi:<a href=\"https://doi.org/10.1101/2020.04.08.029405\">10.1101/2020.04.08.029405</a>","apa":"Grah, R., Zoller, B., &#38; Tkačik, G. (2020). Normative models of enhancer function. <i>bioRxiv</i>. Cold Spring Harbor Laboratory. <a href=\"https://doi.org/10.1101/2020.04.08.029405\">https://doi.org/10.1101/2020.04.08.029405</a>","chicago":"Grah, Rok, Benjamin Zoller, and Gašper Tkačik. “Normative Models of Enhancer Function.” <i>BioRxiv</i>. Cold Spring Harbor Laboratory, 2020. <a href=\"https://doi.org/10.1101/2020.04.08.029405\">https://doi.org/10.1101/2020.04.08.029405</a>.","ieee":"R. Grah, B. Zoller, and G. Tkačik, “Normative models of enhancer function,” <i>bioRxiv</i>. Cold Spring Harbor Laboratory, 2020.","short":"R. Grah, B. Zoller, G. Tkačik, BioRxiv (2020).","mla":"Grah, Rok, et al. “Normative Models of Enhancer Function.” <i>BioRxiv</i>, Cold Spring Harbor Laboratory, 2020, doi:<a href=\"https://doi.org/10.1101/2020.04.08.029405\">10.1101/2020.04.08.029405</a>.","ista":"Grah R, Zoller B, Tkačik G. 2020. Normative models of enhancer function. bioRxiv, <a href=\"https://doi.org/10.1101/2020.04.08.029405\">10.1101/2020.04.08.029405</a>."},"year":"2020","date_updated":"2023-09-07T13:13:26Z","oa":1,"abstract":[{"lang":"eng","text":"In prokaryotes, thermodynamic models of gene regulation provide a highly quantitative mapping from promoter sequences to gene expression levels that is compatible with in vivo and in vitro bio-physical measurements. Such concordance has not been achieved for models of enhancer function in eukaryotes. In equilibrium models, it is difficult to reconcile the reported short transcription factor (TF) residence times on the DNA with the high specificity of regulation. In non-equilibrium models, progress is difficult due to an explosion in the number of parameters. Here, we navigate this complexity by looking for minimal non-equilibrium enhancer models that yield desired regulatory phenotypes: low TF residence time, high specificity and tunable cooperativity. We find that a single extra parameter, interpretable as the “linking rate” by which bound TFs interact with Mediator components, enables our models to escape equilibrium bounds and access optimal regulatory phenotypes, while remaining consistent with the reported phenomenology and simple enough to be inferred from upcoming experiments. We further find that high specificity in non-equilibrium models is in a tradeoff with gene expression noise, predicting bursty dynamics — an experimentally-observed hallmark of eukaryotic transcription. By drastically reducing the vast parameter space to a much smaller subspace that optimally realizes biological function prior to inference from data, our normative approach holds promise for mathematical models in systems biology."}],"day":"09","doi":"10.1101/2020.04.08.029405","status":"public","related_material":{"record":[{"status":"public","id":"8155","relation":"dissertation_contains"}]},"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","main_file_link":[{"url":"https://doi.org/10.1101/2020.04.08.029405 ","open_access":"1"}],"author":[{"id":"483E70DE-F248-11E8-B48F-1D18A9856A87","first_name":"Rok","last_name":"Grah","orcid":"0000-0003-2539-3560","full_name":"Grah, Rok"},{"last_name":"Zoller","first_name":"Benjamin","full_name":"Zoller, Benjamin"},{"last_name":"Tkačik","first_name":"Gašper","full_name":"Tkačik, Gašper","orcid":"0000-0002-6699-1455","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87"}],"_id":"7675","publication":"bioRxiv","title":"Normative models of enhancer function","month":"04","article_processing_charge":"No","date_created":"2020-04-23T10:12:51Z","project":[{"_id":"2665AAFE-B435-11E9-9278-68D0E5697425","name":"Can evolution minimize spurious signaling crosstalk to reach optimal performance?","grant_number":"RGP0034/2018"},{"_id":"267C84F4-B435-11E9-9278-68D0E5697425","name":"Biophysically realistic genotype-phenotype maps for regulatory networks"}],"department":[{"_id":"CaGu"},{"_id":"GaTk"}],"oa_version":"Preprint","publication_status":"published","language":[{"iso":"eng"}],"publisher":"Cold Spring Harbor Laboratory"}]