Partner: James Boyd


Recent publications
1.Bagnall J., Boddington C., England H., Brignall R., Downton P., Alsoufi Z., Boyd J., Rowe W., Bennett A., Walker C., Adamson A., Patel Nisha M. X., O’Cualain R., Schmidt L., Spiller David G., Jackson Dean A., Müller W., Muldoon M., White Michael R. H.R., Paszek P., Quantitative analysis of competitive cytokine signaling predicts tissue thresholds for the propagation of macrophage activation, Science Signaling, ISSN: 1945-0877, DOI: 10.1126/scisignal.aaf3998, Vol.11, No.540, pp.1-15, 2018
Abstract:

Toll-like receptor (TLR) signaling regulates macrophage activation and effector cytokine propagation in the constrained environment of a tissue. In macrophage populations, TLR4 stimulates the dose-dependent transcription of nuclear factor κB (NF-κB) target genes. However, using single-RNA counting, we found that individual cells exhibited a wide range (three orders of magnitude) of expression of the gene encoding the proinflammatory cytokine tumor necrosis factor–α (TNF-α). The TLR4-induced TNFA transcriptional response correlated with the extent of NF-κB signaling in the cells and their size. We compared the rates of TNF-α production and uptake in macrophages and mouse embryonic fibroblasts and generated a mathematical model to explore the heterogeneity in the response of macrophages to TLR4 stimulation and the propagation of the TNF-α signal in the tissue. The model predicts that the local propagation of the TLR4-dependent TNF-α response and cellular NF-κB signaling are limited to small distances of a few cell diameters between neighboring tissue-resident macrophages. In our predictive model, TNF-α propagation was constrained by competitive uptake of TNF-α from the environment, rather than by heterogeneous production of the cytokine. We propose that the highly constrained architecture of tissues enables effective localized propagation of inflammatory cues while avoiding out-of-context responses at longer distances.

Affiliations:
Bagnall J.-other affiliation
Boddington C.-other affiliation
England H.-other affiliation
Brignall R.-other affiliation
Downton P.-other affiliation
Alsoufi Z.-other affiliation
Boyd J.-other affiliation
Rowe W.-other affiliation
Bennett A.-other affiliation
Walker C.-other affiliation
Adamson A.-other affiliation
Patel Nisha M. X.-other affiliation
O’Cualain R.-other affiliation
Schmidt L.-other affiliation
Spiller David G.-other affiliation
Jackson Dean A.-other affiliation
Müller W.-other affiliation
Muldoon M.-other affiliation
White Michael R. H.R.-University of Manchester (GB)
Paszek P.-other affiliation
2.Ankers John M., Awais R., Jones Nicholas A., Boyd J., Ryan S., Adamson Antony D., Harper Claire V.V., Bridge L., Spiller David G., Jackson Dean A., Paszek P., Sée V., White Michael R.R., Dynamic NF-κB and E2F interactions control the priority and timing of inflammatory signalling and cell proliferation, eLife, ISSN: 2050-084X, DOI: 10.7554/eLife.10473, Vol.5, pp.e10473-1-35, 2016
Abstract:

Dynamic cellular systems reprogram gene expression to ensure appropriate cellular fate responses to specific extracellular cues. Here we demonstrate that the dynamics of Nuclear Factor kappa B (NF-κB) signalling and the cell cycle are prioritised differently depending on the timing of an inflammatory signal. Using iterative experimental and computational analyses, we show physical and functional interactions between NF-κB and the E2 Factor 1 (E2F-1) and E2 Factor 4 (E2F-4) cell cycle regulators. These interactions modulate the NF-κB response. In S-phase, the NF-κB response was delayed or repressed, while cell cycle progression was unimpeded. By contrast, activation of NF-κB at the G1/S boundary resulted in a longer cell cycle and more synchronous initial NF-κB responses between cells. These data identify new mechanisms by which the cellular response to stress is differentially controlled at different stages of the cell cycle.

Affiliations:
Ankers John M.-other affiliation
Awais R.-other affiliation
Jones Nicholas A.-Massachusetts Institute of Technology (US)
Boyd J.-other affiliation
Ryan S.-other affiliation
Adamson Antony D.-other affiliation
Harper Claire V.V.-University of Manchester (GB)
Bridge L.-other affiliation
Spiller David G.-other affiliation
Jackson Dean A.-other affiliation
Paszek P.-other affiliation
Sée V.-other affiliation
White Michael R.R.-University of Manchester (GB)
3.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:
Phillips N.-other affiliation
Manning C.-other affiliation
Pettini T.-other affiliation
Veronica B.-other affiliation
Elli M.-other affiliation
Peter S.-other affiliation
Boyd J.-other affiliation
Bagnall J.-other affiliation
Paszek P.-IPPT PAN
Spiller David G.-other affiliation
White M.-other affiliation
Goodfellow M.-other affiliation
Tobias G.-other affiliation
Magnus R.-other affiliation
Nancy P.-other affiliation