Publikation: Long lived transients in gene regulation
Dateien
Datum
Autor:innen
Herausgeber:innen
ISSN der Zeitschrift
Electronic ISSN
ISBN
Bibliografische Daten
Verlag
Schriftenreihe
Auflagebezeichnung
URI (zitierfähiger Link)
DOI (zitierfähiger Link)
Internationale Patentnummer
Link zur Lizenz
Angaben zur Forschungsförderung
Projekt
Open Access-Veröffentlichung
Core Facility der Universität Konstanz
Titel in einer weiteren Sprache
Publikationstyp
Publikationsstatus
Erschienen in
Zusammenfassung
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 synchronization 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 behavior 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 behavior 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 memorize 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.
Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
Schlagwörter
Konferenz
Rezension
Zitieren
ISO 690
PETROV, Tatjana, Claudia IGLER, Ali SEZGIN, Thomas A. HENZINGER, Calin C. GUET, 2021. Long lived transients in gene regulation. In: Theoretical Computer Science. Elsevier. 2021, 893, pp. 1-16. ISSN 0304-3975. eISSN 1879-2294. Available under: doi: 10.1016/j.tcs.2021.05.023BibTex
@article{Petrov2021-11lived-54514, year={2021}, doi={10.1016/j.tcs.2021.05.023}, title={Long lived transients in gene regulation}, volume={893}, issn={0304-3975}, journal={Theoretical Computer Science}, pages={1--16}, author={Petrov, Tatjana and Igler, Claudia and Sezgin, Ali and Henzinger, Thomas A. and Guet, Calin C.} }
RDF
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#" xmlns:foaf="http://xmlns.com/foaf/0.1/" xmlns:void="http://rdfs.org/ns/void#" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/server/rdf/resource/123456789/54514"> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-08-09T09:21:31Z</dc:date> <dc:rights>Attribution-NonCommercial-NoDerivatives 4.0 International</dc:rights> <dc:creator>Sezgin, Ali</dc:creator> <dc:contributor>Henzinger, Thomas A.</dc:contributor> <dc:contributor>Igler, Claudia</dc:contributor> <dcterms:abstract xml:lang="eng">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 synchronization 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 behavior 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 behavior 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 memorize 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.</dcterms:abstract> <foaf:homepage rdf:resource="http://localhost:8080/"/> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/54514"/> <dc:creator>Guet, Calin C.</dc:creator> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/36"/> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/43615"/> <dcterms:title>Long lived transients in gene regulation</dcterms:title> <dc:contributor>Guet, Calin C.</dc:contributor> <dc:contributor>Sezgin, Ali</dc:contributor> <dc:creator>Henzinger, Thomas A.</dc:creator> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/43615"/> <dc:creator>Igler, Claudia</dc:creator> <dc:creator>Petrov, Tatjana</dc:creator> <dcterms:issued>2021-11</dcterms:issued> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-08-09T09:21:31Z</dcterms:available> <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/54514/1/Petrov_2-1uf5e49e7ocli5.pdf"/> <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/54514/1/Petrov_2-1uf5e49e7ocli5.pdf"/> <dc:language>eng</dc:language> <dc:contributor>Petrov, Tatjana</dc:contributor> <dcterms:rights rdf:resource="http://creativecommons.org/licenses/by-nc-nd/4.0/"/> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/36"/> </rdf:Description> </rdf:RDF>