Paszek, Pawel, Ryan, Sheila, Ashall, Louise, Sillitoe, Kate, Harper, Claire V., Spiller, David G., Rand, D. A. (David A.) and White, Michael R. H.. (2010) Population robustness arising from cellular heterogeneity. Proceedings of the National Academy of Sciences of the United States of America, Vol.107 (No.25). pp. 11644-11649. ISSN 0027-8424

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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-kappa B signaling system, the precise timing of a dual-delayed negative feedback motif [involving stochastic transcription of inhibitor kappa B (I kappa B)-alpha and -epsilon] is optimized to induce heterogeneous timing of NF-kappa B oscillations between individual cells. We suggest that this dual-delayed negative feedback motif enables NF-kappa B 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.

Item Type:	Journal Article
Subjects:	Q Science
Divisions:	Faculty of Science > Mathematics Faculty of Science > Centre for Systems Biology
Journal or Publication Title:	Proceedings of the National Academy of Sciences of the United States of America
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date:	22 June 2010
Volume:	Vol.107
Number:	No.25
Number of Pages:	6
Page Range:	pp. 11644-11649
Identification Number:	10.1073/pnas.0913798107
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Medical Research Council (Great Britain) (MRC), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Engineering and Physical Sciences Research Council (EPSRC), European Union
Grant number:	G0500346, BBF0059381/BBF0058141, EP/C544587/1, GR/S29256/01, 005137
URI:	http://wrap.warwick.ac.uk/id/eprint/5634

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