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Title: The effects of intrinsic noise on the behaviour of bistable cell regulatory systems under quasi-steady state conditions

We analyse the effect of intrinsic fluctuations on the properties of bistable stochastic systems with time scale separation operating under quasi-steady state conditions. We first formulate a stochastic generalisation of the quasi-steady state approximation based on the semi-classical approximation of the partial differential equation for the generating function associated with the chemical master equation. Such approximation proceeds by optimising an action functional whose associated set of Euler-Lagrange (Hamilton) equations provides the most likely fluctuation path. We show that, under appropriate conditions granting time scale separation, the Hamiltonian can be re-scaled so that the set of Hamilton equations splits up into slow and fast variables, whereby the quasi-steady state approximation can be applied. We analyse two particular examples of systems whose mean-field limit has been shown to exhibit bi-stability: an enzyme-catalysed system of two mutually inhibitory proteins and a gene regulatory circuit with self-activation. Our theory establishes that the number of molecules of the conserved species is order parameters whose variation regulates bistable behaviour in the associated systems beyond the predictions of the mean-field theory. This prediction is fully confirmed by direct numerical simulations using the stochastic simulation algorithm. This result allows us to propose strategies whereby, by varying the numbermore » of molecules of the three conserved chemical species, cell properties associated to bistable behaviour (phenotype, cell-cycle status, etc.) can be controlled.« less
Authors:
;  [1] ;  [2] ;  [3] ;  [4] ;  [5]
  1. Centre de Recerca Matemàtica. Edifici C, Campus de Bellaterra, 08193 Bellaterra (Barcelona) (Spain)
  2. (Barcelona) (Spain)
  3. Department of Mathematics, University College London, Gower Street, London WC1E 6BT (United Kingdom)
  4. Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, Massachusetts 02215 (United States)
  5. (United States)
Publication Date:
OSTI Identifier:
22493530
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Chemical Physics; Journal Volume: 143; Journal Issue: 7; Other Information: (c) 2015 AIP Publishing LLC; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSICS; ALGORITHMS; CELL CYCLE; COMPUTERIZED SIMULATION; ENZYMES; FLUCTUATIONS; GENES; HAMILTONIANS; MEAN-FIELD THEORY; MOLECULES; NOISE; ORDER PARAMETERS; PARTIAL DIFFERENTIAL EQUATIONS; PHASE STABILITY; PHENOTYPE; STEADY-STATE CONDITIONS; STOCHASTIC PROCESSES