{"oa":1,"publisher":"Elsevier","file":[{"file_size":2566504,"date_created":"2022-05-12T12:13:27Z","date_updated":"2022-05-12T12:13:27Z","creator":"dernst","checksum":"d3aef34cfb13e53bba4cf44d01680793","access_level":"open_access","relation":"main_file","content_type":"application/pdf","file_name":"2021_TheoreticalComputerScience_Petrov.pdf","success":1,"file_id":"11364"}],"doi":"10.1016/j.tcs.2021.05.023","file_date_updated":"2022-05-12T12:13:27Z","acknowledgement":"Tatjana Petrov’s research was supported in part by SNSF Advanced Postdoctoral Mobility Fellowship grant number P300P2 161067, the Ministry of Science, Research and the Arts of the state of Baden-Wurttemberg, and the DFG Centre of Excellence 2117 ‘Centre for the Advanced Study of Collective Behaviour’ (ID: 422037984). Claudia Igler is the recipient of a DOC Fellowship of the Austrian Academy of Sciences. Thomas A. Henzinger’s research was supported in part by the Austrian Science Fund (FWF) under grant Z211-N23 (Wittgenstein Award).","abstract":[{"lang":"eng","text":"Gene expression is regulated by the set of transcription factors (TFs) that bind to the promoter. The ensuing regulating function is often represented as a combinational logic circuit, where output (gene expression) is determined by current input values (promoter bound TFs) only. However, the simultaneous arrival of TFs is a strong assumption, since transcription and translation of genes introduce intrinsic time delays and there is no global synchronisation among the arrival times of different molecular species at their targets. We present an experimentally implementable genetic circuit with two inputs and one output, which in the presence of small delays in input arrival, exhibits qualitatively distinct population-level phenotypes, over timescales that are longer than typical cell doubling times. From a dynamical systems point of view, these phenotypes represent long-lived transients: although they converge to the same value eventually, they do so after a very long time span. The key feature of this toy model genetic circuit is that, despite having only two inputs and one output, it is regulated by twenty-three distinct DNA-TF configurations, two of which are more stable than others (DNA looped states), one promoting and another blocking the expression of the output gene. Small delays in input arrival time result in a majority of cells in the population quickly reaching the stable state associated with the first input, while exiting of this stable state occurs at a slow timescale. In order to mechanistically model the behaviour of this genetic circuit, we used a rule-based modelling language, and implemented a grid-search to find parameter combinations giving rise to long-lived transients. Our analysis shows that in the absence of feedback, there exist path-dependent gene regulatory mechanisms based on the long timescale of transients. The behaviour of this toy model circuit suggests that gene regulatory networks can exploit event timing to create phenotypes, and it opens the possibility that they could use event timing to memorise events, without regulatory feedback. The model reveals the importance of (i) mechanistically modelling the transitions between the different DNA-TF states, and (ii) employing transient analysis thereof."}],"date_created":"2021-07-11T22:01:18Z","language":[{"iso":"eng"}],"isi":1,"day":"04","has_accepted_license":"1","article_processing_charge":"No","publication_status":"published","quality_controlled":"1","date_updated":"2023-08-10T14:11:19Z","date_published":"2021-06-04T00:00:00Z","publication_identifier":{"issn":["0304-3975"]},"intvolume":"       893","tmp":{"short":"CC BY-NC-ND (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)"},"author":[{"full_name":"Petrov, Tatjana","last_name":"Petrov","first_name":"Tatjana"},{"full_name":"Igler, Claudia","first_name":"Claudia","id":"46613666-F248-11E8-B48F-1D18A9856A87","last_name":"Igler"},{"last_name":"Sezgin","id":"4C7638DA-F248-11E8-B48F-1D18A9856A87","first_name":"Ali","full_name":"Sezgin, Ali"},{"first_name":"Thomas A","id":"40876CD8-F248-11E8-B48F-1D18A9856A87","last_name":"Henzinger","orcid":"0000-0002-2985-7724","full_name":"Henzinger, Thomas A"},{"full_name":"Guet, Calin C","orcid":"0000-0001-6220-2052","first_name":"Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","last_name":"Guet"}],"type":"journal_article","oa_version":"Published Version","status":"public","publication":"Theoretical Computer Science","ddc":["004"],"volume":893,"project":[{"grant_number":"Z211","call_identifier":"FWF","name":"The Wittgenstein Prize","_id":"25F42A32-B435-11E9-9278-68D0E5697425"}],"year":"2021","article_type":"original","scopus_import":"1","_id":"9647","citation":{"short":"T. Petrov, C. Igler, A. Sezgin, T.A. Henzinger, C.C. Guet, Theoretical Computer Science 893 (2021) 1–16.","chicago":"Petrov, Tatjana, Claudia Igler, Ali Sezgin, Thomas A Henzinger, and Calin C Guet. “Long Lived Transients in Gene Regulation.” <i>Theoretical Computer Science</i>. Elsevier, 2021. <a href=\"https://doi.org/10.1016/j.tcs.2021.05.023\">https://doi.org/10.1016/j.tcs.2021.05.023</a>.","ama":"Petrov T, Igler C, Sezgin A, Henzinger TA, Guet CC. Long lived transients in gene regulation. <i>Theoretical Computer Science</i>. 2021;893:1-16. doi:<a href=\"https://doi.org/10.1016/j.tcs.2021.05.023\">10.1016/j.tcs.2021.05.023</a>","ista":"Petrov T, Igler C, Sezgin A, Henzinger TA, Guet CC. 2021. Long lived transients in gene regulation. Theoretical Computer Science. 893, 1–16.","ieee":"T. Petrov, C. Igler, A. Sezgin, T. A. Henzinger, and C. C. Guet, “Long lived transients in gene regulation,” <i>Theoretical Computer Science</i>, vol. 893. Elsevier, pp. 1–16, 2021.","mla":"Petrov, Tatjana, et al. “Long Lived Transients in Gene Regulation.” <i>Theoretical Computer Science</i>, vol. 893, Elsevier, 2021, pp. 1–16, doi:<a href=\"https://doi.org/10.1016/j.tcs.2021.05.023\">10.1016/j.tcs.2021.05.023</a>.","apa":"Petrov, T., Igler, C., Sezgin, A., Henzinger, T. A., &#38; Guet, C. C. (2021). Long lived transients in gene regulation. <i>Theoretical Computer Science</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.tcs.2021.05.023\">https://doi.org/10.1016/j.tcs.2021.05.023</a>"},"month":"06","page":"1-16","department":[{"_id":"ToHe"},{"_id":"CaGu"}],"external_id":{"isi":["000710180500002"]},"title":"Long lived transients in gene regulation","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8"}