January 30, 2014
Imagine you run a railroad that has a single track. You need for trains to run in both directions to get your cargo where it needs to go.
One way to regulate this might be to have the trains just go whenever and count on collisions as a way to regulate traffic. Talk about a poor business model! Odds are your company would quickly go bankrupt.
Another, more sane possibility is to somehow keep the trains from running into each other. Maybe you schedule them so their paths never cross. Or maybe you have small detours where a train can wait while the other passes. Anything is better than regulation by wreckage!
Turns out that at least in some cases, nature is a better business person than many people previously thought. Instead of trains on a track, nature needs to deal with nearby genes that point towards one another, so-called convergent genes. If both genes are expressed, then the RNA polymerases will barrel towards one another and could collide.
A new study in PLoS Genetics by Wang and coworkers shows just how big a deal this issue is for our favorite yeast Saccharomyces cerevisiae. An analysis of this yeast’s genome showed that not only did 20% of its genes fit the convergent definition but that in many cases, each gene in a pair influenced the expression of the other gene. Their expression was negatively correlated: when one of the pair was turned up, the other went down, and vice versa.
One way these genes might regulate one another is the collision model. When expression of one gene is turned up and a lot of RNA polymerases are barreling down the tracks, they would crash into and derail any polymerases coming from the opposite direction. A prediction of this model is that orientation and location matter. In other words, the negative regulation would work only in cis, not in trans. Surprisingly, the authors show that this is clearly not the case.
Focusing on four different gene pairs, Wang and coworkers showed that if the genes in a pair were physically separated from one another, their expression was still negatively correlated. This was true if they just flipped one of the genes so the two genes were pointed in the same direction, and it was still true if they moved one gene to a different chromosome. Clearly, collisions were not the only way these genes regulated one another.
Using missense and deletion mutation analysis, the authors showed that neither the proteins from these genes nor the coding sequence itself was required for this regulation. Instead, the key player was the overlapping 3’ untranslated regions (UTRs) of the transcripts. The authors hypothesize that the regulation is happening via an anti-sense mechanism using the complementary portions of the 3’ UTRs.
This anti-sense mechanism may be S. cerevisiae’s answer to RNAi, which it lost at some point in its evolutionary history. Given the importance of RNA-mediated regulation of gene expression in other organisms, perhaps it shouldn’t be surprising that yeast has come up with another way to use RNA.
Instead of RNAi, it relies on genomic structure and overlapping 3’ UTRs to regulate genes. This may be a bit more cumbersome than RNAi, but at least yeast came up with a more clever system than polymerase collisions to regulate gene expression.
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics
Categories: Research Spotlight