Surprisingly sloppy yeast genes
The findings suggest the current understanding of transcription networks should be reassessed
Contrary to popular belief, the gene expression of "housekeeping" proteins in yeast is not synchronized or even coordinated.
Instead, these essential genes -- which work together to build important cell complexes like ribosomes and proteasomes -- are turned on and off randomly, researchers report in today's online edition of linkurl:Nature Structural and Molecular Biology
|Fluorescent micrograph of Saccharomyces cerevisiae |
linkurl:Philippsen Lab, Biozentrum Basel;http://commons.wikimedia.org/wiki/File:S_cerevisiae_septins.jpg
"We all have our biases about how things work," said senior author linkurl:Robert Singer;http://www.singerlab.org/ of the Albert Einstein College of Medicine in New York. "Sometimes, we're just wrong."
The surprising finding may change the way scientists understand and assess some gene transcription networks.
"It's fantastic work," said linkurl:Mads Kaern,;http://www.sysbiolab.uottawa.ca/ Canada Research Chair in systems biology at the University of Ottawa, who was not involved in the research. "This challenges the idea that elaborate networks have evolved to regulate this class of genes. That is profound."
Multi-protein complexes -- like ribosomes, made up of 80 different proteins -- perform essential functions in cells. Scientists have long assumed the expression of the genes required to assemble such complexes is coordinated because often the resulting proteins have similar abundances in cells. Additionally, it made logical sense that widely varying levels of subunits would result in malformed complexes or a build-up of toxic levels of unused proteins.
But linkurl:in 2008,;http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&term=Single-RNA+counting+reveals+alternative+modes+of+gene+expression+in+yeast. Singer and colleagues studying the expression of genes in yeast noticed that many constitutive genes -- those transcribed throughout the cell cycle rather than on an as-needed basis -- had irregular, random expression patterns. The unexpected finding led them to predict that the expression of genes needed for multi-protein complexes might not be synchronized, either.
When the team measured the expression of several groups of genes -- those encoding subunits of a proteasome, a transcription factor, and RNA polymerase II -- they found that the mRNAs of each group's subunits were no more correlated than the mRNAs of genes that had no functional relationship to each other. Even two alleles of the same gene with identical promoters were not expressed equally.
"The genes are essentially clueless," said Singer. "They don't know what they're making or the actual destiny of protein. They're just there, cranking out proteins." In contrast, induced genes -- those triggered by stimuli, such as a nearby toxin or nutrient-rich media -- demonstrated highly coordinated expression.
Consequently, the researchers assume that the coordination of protein abundances for complexes happens after transcription. Because many proteins have longer half-lives than mRNA, for example, random fluctuations in mRNA levels may be inconsequential because proteins stick around for significantly longer. Or perhaps chaperone molecules impose checkpoints, stabilizing ribosomes or proteasomes to prevent dissociation until the next subunit arrives. Or both.
"We have this bias about cells being efficient, but the more we learn about them, the more inefficient we find out they are," said Singer. "But maybe that's the way biological systems have to work. If they had too many controls, there's a lot more opportunity for things to go wrong."
The un-coordinated expression of constitutive genes may have an important evolutionary function, suggested Kaern. "They may make cells more robust, less sensitive to mutations in upstream regulators," he said. If constitutive genes shared one upstream activator to turn them all on simultaneously, a single mutation in that activator could have catastrophic consequences for the cell, he speculated.
Overall, the research has important implications for systems biology and researchers studying gene networks of constitutive genes. "This opens up a conceptual door that was previously ignored," said Kaern, who suspects something similar may occur in mice and human cells. "But I think a lot of yeast biologists will not be surprised [this happens in yeast] because they know how sloppy yeast is," he added. "It has a tendency to survive whatever you throw at it."
Gandhi, S.J. et al., "Transcription of functionally related constitutive genes is not coordinated," Nat Struct Mol Biol., published online 5 December 2010, doi: 10.1038/nsmb.1934
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[23rd March 2010]