Pulsating Mechanism as a Stress Response

Genomes are not merely consisting of A,T, G and C. There is so lot more to them than we know. A comparatively simpler genome of a bacteria like Bacillus subtilis can respond to a wide array of changes in its environment. Our knowledge of the exact mechanism is not complete as yet since there is a need for a better system of studying gene-protein interaction. Take, for instance the stress response that bacteria take in cold. While we resort to heaters for tackling the cold, the bacteria does the same! This is what has been reported recently by researchers at Caltech.

Fig: Florescent proteins are used to study the pulsating mechanism.

Previously we assumed that in response to stress, bacteria generally go to a dormant state-meaning that they shift from one state to another. However, new studies shows an active utilization of the existing system to tackle the stress.

What the researchers say?

Researchers at the California Institute of Technology (Caltech) are finding that cells can respond using a new kind of pulsating mechanism, instead of just shifting from one steady state to another and staying there. The principles behind this process are surprisingly simple, the researchers say, and could drive other cellular processes, revealing more about how the cells—and ultimately life—work.

The Experiment

In their experiment, the researchers studied how a bacterial species called B. subtilis responds to a stressful environment—for example, one without food. In such conditions, the single-celled organism activates a large set of genes that help it deal with hardship, by aiding cell repair for instance. Previously, biologists had thought the bacteria would handle stress by turning on the relevant genes and simply leaving them on until the stress goes away.

Instead, the researchers found that B. subtilis continuously flips these genes on and off. When faced with more stress, it increases the frequency of these pulses. The pulsating action is like switching your heater on full blast for a brief period every few minutes, and turning it on and off more frequently if you want the house to be warmer.

The Underlying Mechanism: Genetic Circuit

To make their finding, the researchers introduced a chemical to B. subtilis that inhibits the production of ATP, the energy-carrying molecules of cells. The team found that the stress induced by this chemical triggers interactions within a set of genes—collectively called a genetic circuit. This circuit, which contains a set of positive and negative feedback loops, generates sustained pulses of activity in a key regulatory protein called σB  (“sigma B”). The researchers attached fluorescent proteins to the circuit, causing the cells to glow green when σB was activated. By making movies of the flashing cells, the team could then study the dynamics of the circuit.

The key to this pulsating mechanism is the variability inherent in how proteins are made, the researchers say. The number of copies of any specific protein in a given cell fluctuates over time. The bacterial gene circuit amplifies these molecular fluctuations, also called noise, to generate discrete pulses of σB activation. The stress also activates another key protein that modulates the pulse frequencies.

More on the Genetic Circuit

By turning a steady input (the stress) into an oscillating output (the activation of σB) the genetic circuit is analogous to an electrical inverter, a device that converts direct current (DC) into alternating current (AC), explains Michael Elowitz, professor of biology and bioengineering at Caltech, Howard Hughes Medical Institute investigator, and coauthor of the paper. “You might think you need some kind of elaborate circuitry to implement that, but the cell can do it with just a few proteins, and by taking advantage of noise.”

This work provides a blueprint for how relatively simple genetic circuits can generate complex and dynamic behaviors in individual cells, the researchers say. “We’re excited to think that similar mechanisms may occur in other cellular processes,” Locke says. “It’d be interesting in the future to see which aspects of this circuit architecture also appear in more complex systems, such as mammalian cells.”

The paper has been titled “Stochastic pulse regulation in bacterial stress response” and was published in Science in October. (http://www.ncbi.nlm.nih.gov/pubmed/21979936)

-Caltech Media Relations

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