Molecular managers call the shots
YALE (US)—Similar to the way things work in social hierarchies, some molecular organisms give orders and some carry them out.
Knowing these organizational rules will help understand biological systems and social interactions, says Mark Gerstein, A.L. Williams professor of biomedical informatics, molecular biophysics, and biochemistry and computer science, at Yale University.
Gerstein analyzed the regulatory networks of five diverse species, from E. coli to human, and rearranged them into broad leveled hierarchies, including “master regulators,” “middle managers,” and “workhorses.”
In most organisms, he says, master regulators control the activity of middle managers, which in turn govern suites of workhorse genes that carry out instructions for making proteins.
Details of the study were published online in the Proceedings of the National Academy of Sciences.
As a general rule, the more complex the organism, the less autocratic and more democratic the biological networks appear to be, Gerstein says.
In both biological systems and corporate structures, interactions between middle managers are often more critical to functioning than actions by bosses.
“If my department chair takes another job, the emphasis of my lab might change, but it will survive,” Gerstein explains. “But if my systems administrator leaves, my lab dies.”
In simple “autocratic” organisms such as E. coli, there tends to be a chain of command in which regulatory genes act like generals, and subordinate molecules “downstream” follow a single superior’s instructions.
But in more complex “democratic” organisms, most of these subordinate genes co-regulate biological activity, in a sense sharing information and collaborating in governance.
Organisms that have both qualities are deemed “intermediate.”
The interactions in more democratic hierarchies lead to mutually supporting partnerships between regulators than in autocratic systems, where if one gene is inactivated, the system tends to collapse.
This is why Gerstein and colleagues in earlier work found that when they knocked out a master regulating gene in a complex organism, the “effects were more global, but softer” than when a key middle manager gene in a simpler life form was inactivated, which led to the death of the organism.
“Regulators in more complex species demonstrate a highly collaborative nature. We believe that these are due to the size and complexity of these genomes.”
As an example, Gerstein says about 250 master regulators in yeast have 6,000 potential targets, a ratio of about one to 25, compared with humans, in which 20,000 targets are regulated by about 2,000 genes, a ratio of one to 10.
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