Partner: Sheila Ryan


Recent publications
1.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)
2.Paszek P., Ryan S., Ashall L., Sillitoe K., Harper C. V., Spiller David G., Rand D. A., White M., Population robustness arising from cellular heterogeneity, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, ISSN: 0027-8424, DOI: 10.1073/pnas.0913798107, Vol.107, No.25, pp.11644-11649, 2010
Abstract:

Heterogeneity between individual cells is a common feature of dynamic cellular processes, including signaling, transcription, and cell fate; yet the overall tissue level physiological phenotype needs to be carefully controlled to avoid fluctuations. Here we show that in the NF-κB signaling system, the precise timing of a dual-delayed negative feedback motif [involving stochastic transcription of inhibitor κB (IκB)-α and -ε] is optimized to induce heterogeneous timing of NF-κB oscillations between individual cells. We suggest that this dual-delayed negative feedback motif enables NF-κB signaling to generate robust single cell oscillations by reducing sensitivity to key parameter perturbations. Simultaneously, enhanced cell heterogeneity may represent a mechanism that controls the overall coordination and stability of cell population responses by decreasing temporal fluctuations of paracrine signaling. It has often been thought that dynamic biological systems may have evolved to maximize robustness through cell-to-cell coordination and homogeneity. Our analyses suggest in contrast, that this cellular variation might be advantageous and subject to evolutionary selection. Alternative types of therapy could perhaps be designed to modulate this cellular heterogeneity.

Affiliations:
Paszek P.-IPPT PAN
Ryan S.-other affiliation
Ashall L.-other affiliation
Sillitoe K.-other affiliation
Harper C. V.-University of Manchester (GB)
Spiller David G.-other affiliation
Rand D. A.-University of Warwick (GB)
White M.-other affiliation
3.Ashall L., Horton Caroline A., Nelson David E., Paszek P., Harper Claire V.V., Sillitoe K., Ryan S., Spiller David G., Unitt John F., Broomhead David S., Kell Douglas B., Rand David A.A., Sée V., White Michael R.R., Pulsatile Stimulation Determines Timing and Specificity of NF-κB-Dependent Transcription, Science, ISSN: 0036-8075, DOI: 10.1126/science.1164860, Vol.324, No.5924, pp.242-246, 2009
Abstract:

The nuclear factor κB (NF-κB) transcription factor regulates cellular stress responses and the immune response to infection. NF-κB activation results in oscillations in nuclear NF-κB abundance. To define the function of these oscillations, we treated cells with repeated short pulses of tumor necrosis factor–α at various intervals to mimic pulsatile inflammatory signals. At all pulse intervals that were analyzed, we observed synchronous cycles of NF-κB nuclear translocation. Lower frequency stimulations gave repeated full-amplitude translocations, whereas higher frequency pulses gave reduced translocation, indicating a failure to reset. Deterministic and stochastic mathematical models predicted how negative feedback loops regulate both the resetting of the system and cellular heterogeneity. Altering the stimulation intervals gave different patterns of NF-κB–dependent gene expression, which supports the idea that oscillation frequency has a functional role.

Affiliations:
Ashall L.-other affiliation
Horton Caroline A.-other affiliation
Nelson David E.-other affiliation
Paszek P.-other affiliation
Harper Claire V.V.-University of Manchester (GB)
Sillitoe K.-other affiliation
Ryan S.-other affiliation
Spiller David G.-other affiliation
Unitt John F.-other affiliation
Broomhead David S.-other affiliation
Kell Douglas B.-other affiliation
Rand David A.A.-University of Warwick (GB)
Sée V.-other affiliation
White Michael R.R.-University of Manchester (GB)