HOW TO INFER CELLULAR RESPONSE TO A SMALL STIMULUS FROM BEHAVIORAL VARIABILITY BEFORE STIMULUS IN BACTERIA
January 14th, 2011
Over the last decade, there has been a series of remarkable studies dealing with the characterization of noise in gene regulatory networks and signaling pathways. However, noise has often been regarded as a nuisance that affects cellular behavior and that can be reduced by the use of feedback loops. By contrast, our study is using a unifying framework to establish that in some cases cellular response to stimuli and noise are interdependent traits. We can intuitively understand this result if we assume that the sensitivity of some biological systems (i.e. pathways) to intracellular noise is also an indication of their sensitivity to small extra-cellular perturbations, such as sudden changes in the environment. We experimentally prove the existence of this relationship between the fluctuations of cellular behavior (noise) in single cells and the cellular response to an external stimulus using bacterial chemotaxis in E. coli as a model system.
Chemotaxis in E. coli is a locomotion system that allows bacteria to move towards sources of chemical attractants such as Serine and Aspartate. Long flagellar filaments that act like propellers are powered by rotary motors and govern the motile behavior of bacteria. When bacteria can swim in a liquid environment, they exhibit either long smooth runs or abrupt stops, called tumbles, during which cells change randomly direction. Bacteria use this strategy of random walk to search for a better environment. The chemotaxis pathway, one of the best-characterized signal transduction networks, controls the frequency of tumbles. One hallmark of this pathway is adaptation: Following a stepwise stimulus, the tumbling frequency decreases abruptly, before slowly adapting back to its pre-stimulus level. The duration of this adaptive response is defined as the cellular response.
Our study demonstrates that the noise (i.e. fluctuations) in tumbling frequency before stimulus is proportional to the cellular response to a small stimulus. Large noise is associated with long response. Interestingly, we find that this relationship between noise and cellular response is the consequence of a fundamental theorem in physics called the fluctuation-response theorem. Therefore this relationship should not depend on the specific molecular details of the chemotaxis pathways but rather be applicable to a large class of signaling networks.
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