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dc.contributor.authorUnosson, Måns
dc.contributor.authorBrancaccio, Marco
dc.contributor.authorHastings, Michael
dc.contributor.authorJohansen, Adam M
dc.contributor.authorFinkenstädt, Bärbel
dc.date.accessioned2022-02-18T00:30:43Z
dc.date.available2022-02-18T00:30:43Z
dc.date.issued2021-12
dc.identifier.issn1553-734X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/334180
dc.description.abstractWe propose a stochastic distributed delay model together with a Markov random field prior and a measurement model for bioluminescence-reporting to analyse spatio-temporal gene expression in intact networks of cells. The model describes the oscillating time evolution of molecular mRNA counts through a negative transcriptional-translational feedback loop encoded in a chemical Langevin equation with a probabilistic delay distribution. The model is extended spatially by means of a multiplicative random effects model with a first order Markov random field prior distribution. Our methodology effectively separates intrinsic molecular noise, measurement noise, and extrinsic noise and phenotypic variation driving cell heterogeneity, while being amenable to parameter identification and inference. Based on the single-cell model we propose a novel computational stability analysis that allows us to infer two key characteristics, namely the robustness of the oscillations, i.e. whether the reaction network exhibits sustained or damped oscillations, and the profile of the regulation, i.e. whether the inhibition occurs over time in a more distributed versus a more direct manner, which affects the cells' ability to phase-shift to new schedules. We show how insight into the spatio-temporal characteristics of the circadian feedback loop in the suprachiasmatic nucleus (SCN) can be gained by applying the methodology to bioluminescence-reported expression of the circadian core clock gene Cry1 across mouse SCN tissue. We find that while (almost) all SCN neurons exhibit robust cell-autonomous oscillations, the parameters that are associated with the regulatory transcription profile give rise to a spatial division of the tissue between the central region whose oscillations are resilient to perturbation in the sense that they maintain a high degree of synchronicity, and the dorsal region which appears to phase shift in a more diversified way as a response to large perturbations and thus could be more amenable to entrainment.
dc.format.mediumElectronic-eCollection
dc.publisherPublic Library of Science (PLoS)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleA spatio-temporal model to reveal oscillator phenotypes in molecular clocks: Parameter estimation elucidates circadian gene transcription dynamics in single-cells.
dc.typeArticle
dc.publisher.departmentMrc Laboratory of Molecular Biology
dc.date.updated2022-02-17T14:38:01Z
prism.issueIdentifier12
prism.numberARTN e1009698
prism.publicationDate2021
prism.publicationNamePLoS Comput Biol
prism.startingPagee1009698
prism.volume17
dc.identifier.doi10.17863/CAM.81591
dcterms.dateAccepted2021-11-29
rioxxterms.versionofrecord10.1371/journal.pcbi.1009698
rioxxterms.versionVoR
dc.contributor.orcidUnosson, Måns [0000-0001-6649-2288]
dc.contributor.orcidBrancaccio, Marco [0000-0001-8053-5221]
dc.contributor.orcidHastings, Michael [0000-0001-8576-6651]
dc.contributor.orcidJohansen, Adam M [0000-0002-3531-7628]
dc.identifier.eissn1553-7358
rioxxterms.typeJournal Article/Review
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/R034710/1)
cam.issuedOnline2021-12-17
cam.depositDate2022-02-17
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International