Inherent in the idea of gene regulatory networks was the concept that genome sequences that provided information about how genes should be expressed would be as important as the genome sequences that coded for the proteins themselves. Although non-protein-coding DNA was long considered to be “junk,” Davidson recognized that the key regulatory code resided in this genetic material. In 2006, Davidson co-led a group of 240 researchers from more than 70 institutions that sequenced the purple sea urchin’s genome. In 2008, a consortium of institutions led by Davidson’s lab characterized the 23,000 genes of that genome.

In parallel, the Davidson group systematically created a comprehensive functional testing strategy to detect all of the control connections between the genes involved in the key events in the earliest stages of sea urchin embryo development, and to determine how the activity of each gene affected the ability of every other gene in that part of the embryo to be expressed. The network model, first described in 2002 and elucidated and extended over the next 13 years, revealed that the regulatory networks governing high-level processes such as the formation of a specific type of cell are built from gene circuits that can have striking similarities even when the identities of the genes in the circuits are different. These circuits can be viewed as a few dozen types of modules that perform specific functions. Because similar modular systems appear to exist in flies, frogs, chicks, mice, and zebrafish, they may be a universal feature of higher organisms.

When the scientists stressed the yeast cells by adding heat, for example, or restricting food, the pulses of Msn2 and Mig1 changed their timing with respect to one another, with more or less frequent periods of overlap between their pulses, depending upon the stressing stimulus.

Generally, when the two transcription factors pulsed in synchrony, the repressor blocked the ability of the activator to turn on genes. “It’s like someone simultaneously pumping the gas and brake pedals in a car over and over again,” says Elowitz.

But when they were off-beat, with the activator pulsing without the repressor, gene expression increased. “When the cell alternates between the brake and the gas—the Msn2 transcription factor in this case—the car can move,” says Elowitz. As a result of these stress-altered rhythms, the cells successfully produced more (or fewer) copies of certain proteins that helped the yeast cope with the unpleasant situation.

Previously, researchers have thought that the relative concentrations of multiple transcription factors in the nucleus determine how they regulate a common gene target—a phenomenon known as combinatorial regulation. But the new study suggests that the relative timing of the pulses of transcription factors may be just as important as their concentration.

“Most genes in the cell are regulated by several transcription factors in a combinatorial fashion, as parts of a complex network,” says Cai. “What we’re now seeing is a new mode of regulation that controls the pulse timing of transcription factors, and this could be critical to understanding the combinatorial regulation in genetic networks.”

“There appears to be a layer of time-based regulation in the cell that, because it can only be observed with movies of individual cells, is still largely unexplored,” says Lin. “We look forward to learning more about this intriguing and underappreciated form of gene regulation.”

In future research, the scientists will try to understand how prevalent this newfound mode of time-based regulation is in a variety of cell types and will examine its involvement in gene regulation systems. In the context of synthetic biology—the harnessing and modification of biological systems for human technological applications—the researchers also hope to develop methods to control such pulsing to program new cellular behaviors.

Original News : phys.org

Original Paper: The Elowitz Lab