Partner: Michael R.H White |
Recent publications
1. | Phillips N.♦, Manning C.♦, Pettini T.♦, Veronica B.♦, Elli M.♦, Peter S.♦, Boyd J.♦, Bagnall J.♦, Paszek P., Spiller David G.♦, White M.♦, Goodfellow M.♦, Tobias G.♦, Magnus R.♦, Nancy P.♦, Stochasticity in the miR-9/Hes1 oscillatory network can account for clonal heterogeneity in the timing of differentiation, eLife, ISSN: 2050-084X, DOI: 10.7554/eLife.16118, Vol.5, pp.e16118-1-33, 2016 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 the Hes1/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. Affiliations:
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2. | Yunjiao W.♦, Paszek P., Horton Caroline A.♦, Hong Y.♦, White M.♦, Kell Douglas B.♦, Muldoon M.♦, Broomhead David S.♦, A systematic survey of the response of a model NF-kB signalling pathway to TNFa stimulation, JOURNAL OF THEORETICAL BIOLOGY, ISSN: 0022-5193, DOI: 10.1016/j.jtbi.2011.12.014, Vol.297, pp.137-147, 2012 Abstract: White's lab established that strong, continuous stimulation with tumour necrosis factor- () can induce sustained oscillations in the subcellular localisation of the transcription factor nuclear factor (NF-). But the intensity of the signal varies substantially, from picomolar in the blood plasma of healthy organisms to nanomolar in diseased states. We report on a systematic survey using computational bifurcation theory to explore the relationship between the intensity of stimulation and the existence of sustained NF- oscillations. Using a deterministic model developed by Ashall et al. in 2009, we find that the system's responses to are characterised by a supercritical Hopf bifurcation point: above a critical intensity of the system exhibits sustained oscillations in NF-kB localisation. For below this critical value, damped oscillations are observed. This picture depends, however, on the values of the model's other parameters. When the values of certain reaction rates are altered the response of the signalling pathway to stimulation changes: in addition to the sustained oscillations induced by high-dose stimulation, a second oscillatory regime appears at much lower doses. Finally, we define scores to quantify the sensitivity of the dynamics of the system to variation in its parameters and use these scores to establish that the qualitative dynamics are most sensitive to the details of NF- mediated gene transcription. Keywords:NF-kB signalling pathway, Parameter sensitivity, Bifurcation analysis, Oscillations Affiliations:
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3. | Yunjiao W.♦, Paszek P., Horton Caroline A.♦, Kell Douglas B.♦, White M.♦, Broomhead David S.♦, Muldoon M.♦, Interactions among oscillatory pathways in NF-kappa B signaling, BMC SYSTEMS BIOLOGY, ISSN: 1752-0509, DOI: 10.1186/1752-0509-5-23, Vol.5, pp.23-1-11, 2011 Abstract: Background
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4. | Paszek P., Jackson Dean A.♦, White M.♦, Oscillatory control of signalling molecules, Current Opinion in Genetics & Development, ISSN: 0959-437X, DOI: 10.1016/j.gde.2010.08.004, Vol.20, No.6, pp.670-676, 2010 Abstract: The emergence of biological function from the dynamic control of cellular signalling molecules is a fundamental process in biology. Key questions include: How do cells decipher noisy environmental cues, encode these signals to control fate decisions and propagate information through tissues? Recent advances in systems biology, and molecular and cellular biology, exemplified by analyses of signalling via the transcription factor Nuclear Factor kappaB (NF-κB), reveal a critical role of oscillatory control in the regulation of these biological functions. The emerging view is that the oscillatory dynamics of signalling molecules and the epigenetically regulated specificity for target genes contribute to robust regulation of biological function at different levels of cellular organisation through frequency-dependent information encoding.
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