Gene Regulation Includes RNA Peaks and Protein Plateaus

Like latter-day time-and-motion specialists, scientists are scrutinizing the relative contributions to gene expression regulation that are made by the RNA and protein portions of the cellular assembly line. [iStock/Patrick Heagney]

By looking at the cell as a protein factory, scientists hope to understand how a two-stage assembly line—DNA-to-RNA transcription and RNA-to-protein translation—adjusts to changing circumstances. Bringing to mind the time-and-motion specialists of the factory floor, scientists interested in gene regulation are deploying statistical techniques to make sense of fluctuating inventories up and down the chain of production.

Although the scientists agree that gene expression regulation is more intricate than had been assumed previously, there is a difference of opinion as to which assembly line stage is more important overall. That is, the relative contributions of regulation at the RNA level (transcription and RNA degradation) and regulation at the protein level (translation and protein degradation) are subject to ongoing debate.

To shed more light on gene expression regulation, a team of scientists based at New York University decided to see how mammalian cells would respond to what was, essentially, a change in production orders. Specifically, they mapped proteomic and transcriptomic changes in the cells after they had been stressed by dithiothreitol over 30 hours. Dithiothreitol is a reagent that challenges protein folding.

The results of this work appeared January 20 in the journal Molecular Systems Biology in an article entitled “Differential dynamics of the mammalian mRNA and protein expression response to misfolding stress.” Overall, the two regulatory levels were equally important, the scientists found, but the impact of these levels on molecule concentrations differed. Both mRNA and protein changes peaked between two and eight hours, but mRNA expression fold changes were much smaller than those of the proteins.

“mRNA concentrations shifted in a transient, pulse-like pattern and returned to values close to pre-treatment levels by the end of the experiment,” wrote the authors. “In contrast, protein concentrations switched only once and established a new steady state, consistent with the dominant role of protein regulation during misfolding stress.”

Essentially, these results showed notable distinctions between DNA and mRNA in the nature of their signaling. The process of making RNA from DNA was pulse-like—a brief messaging over the studied period that returned to the normal levels by the end of the measurements. By contrast, the process of making a protein from RNA was akin to an on/off switch: Once started, levels remained constant for consistent periods before reverting back to long stretches of dormancy.

While the reasons for these differences in cell behavior remain unknown, the researchers believe the answer may lie in the nature of the two tasks.

“It is very costly for the cell to make proteins, but making RNA messages from DNA is a relatively low-energy and simple process, so it makes sense that we see frequent, or pulsating, signaling at this stage,” observed Christine Vogel, Ph.D., an assistant professor in New York University's Department of Biology and one of the study's senior authors. “By contrast, creating proteins is an intricate undertaking, requiring a great deal of time and energy. This may be why, once you decided to stop production of proteins, you do not turn it back on that easily—and the other way around.”

“We suggest that the way RNA- and protein-level regulation determines the post-treatment homeostatic condition depends on the nature of treatment and its implications on the fitness of the cells; that is, stress conditions versus stimulation,” the authors of the study concluded. “The debate on the relative contribution of transcriptomics and post-transcriptional regulation will have to be continued in a context-specific discourse with systematic comparisons of various conditions.”