title: Stochasticity in the miR-9/Hes1 oscillatory network can account for clonal heterogeneity in the timing of differentiation.
abstract: Recent studies suggest that cells make stochastic choices with respect to differentiation or division. However, the molecular mechanism underlying such stochasticity is unknown. We previously proposed that the timing of vertebrate neuronal differentiation is regulated by molecular oscillations of a transcriptional repressor, HES1, tuned by a post-transcriptional repressor, miR-9. Here, we computationally model the effects of intrinsic noise on theHes1/miR-9 oscillator as a consequence of low molecular numbers of interacting species, determined experimentally. We report that increased stochasticity spreads the timing of differentiation in a population, such that initially equivalent cells differentiate over a period of time. Surprisingly, inherent stochasticity also increases the robustness of the progenitor state and lessens the impact of unequal, random distribution of molecules at cell division on the temporal spread of differentiation at the population level. This advantageous use of biological noise contrasts with the view that noise needs to be counteracted.
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Nick E
authors.initials: NE
authors.lastname: Phillips
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Cerys S
authors.initials: CS
authors.lastname: Manning
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Pettini
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Veronica
authors.initials: V
authors.lastname: Biga
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Elli
authors.initials: E
authors.lastname: Marinopoulou
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Stanley
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Boyd
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Bagnall
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Pawel
authors.initials: P
authors.lastname: Paszek
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: David G
authors.initials: DG
authors.lastname: Spiller
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Michael Rh
authors.identifier: 0000-0002-3617-3232
authors.initials: MR
authors.lastname: White
authors.affiliation: College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, United Kingdom.|Centre for Biomedical Modelling and Analysis, University of Exeter, Exeter, United Kingdom.|EPSRC Centre for Predictive Modelling in Healthcare, University of Exeter, Exeter, United Kingdom.
authors.forename: Marc
authors.identifier: 0000-0002-7282-7280
authors.initials: M
authors.lastname: Goodfellow
authors.affiliation: Theoretical Physics, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom.
authors.forename: Tobias
authors.initials: T
authors.lastname: Galla
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Magnus
authors.initials: M
authors.lastname: Rattray
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Nancy
authors.identifier: 0000-0001-6992-6870
authors.initials: N
authors.lastname: Papalopulu
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D003198:Computer Simulation; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D000072056:Transcription Factor HES-1 / Q000378:metabolism*
chemical_list: C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human
keywords: Hes1; computational biology; developmental biology; miR-9; molecular oscillations; mouse; neural stem cells; single cell heterogeneity; stem cells; stochasticity; systems biology