December 3, 2010 § Leave a comment
Since we only recently found out that microRNAs and small interfering RNAs (siRNAs) exist, and modulate gene expression, it’s perhaps not surprising that many aspects of their function are still puzzling. One mysterious feature is the fact that the efficacy of microRNAs and siRNAs in silencing mRNAs is rather unpredictable. For example, a single microRNA that targets many mRNA transcripts — binding to the same or very similar sites on each one — may shows a very different degree of silencing on different targets. And some targets seem to be resistant to silencing no matter how hard you try. In the past, we’ve looked at this as a problem with the design of microRNAs and siRNAs; perhaps we don’t know how to do it right, yet. But a new paper from Debbie Marks and collaborators (Larsson et al. mRNA turnover limits siRNA and microRNA efficacy. doi:10.1038/msb.2010.89) now shows that at least part of the problem lies in the target, not the silencer: mRNAs that turn over rapidly are far harder to silence significantly than mRNAs that turn over slowly.
Larsson et al. provide a simple mathematical argument to show why they started exploring this idea, and I will reproduce part of this in a minute. But for those who aren’t used to thinking about the mathematical analysis of steady states, here’s an analogy. Suppose that you’ve finally been pushed over the edge by the wasteful, ear-shattering use of leaf blowers in your neighborhood, and you’ve taken the necessary time away from your normal concerns to invent and build a Roomba equivalent for the garden. Now the leaves are falling, and you’re testing it.
September 27, 2010 § 2 Comments
A recent paper from the Bartel and Weissman groups (Guo et al. Mammalian microRNAs predominantly act to decrease target mRNA levels, Nature 466 835-40, PMID: 20703300) provides an interesting snapshot of the journey of a field from consensus to controversy to (one day?) consensus again.
At issue is the question of how microRNAs — small RNAs that control gene expression — have their effect. Clearly they bind specifically to messenger RNAs that carry a short target sequence; clearly, the overall result is that a reduced amount of protein is expressed from the targeted mRNA. But is the translation of the mRNA blocked, or is the mRNA itself destabilized, or both? The answer could affect everything from the way you measure an miRNA effect to the way you think about choosing targets for therapeutic applications. And the consensus in the field seems to be swinging fairly hard — or has swung, depending on who you talk to — from one extreme (the main effect is on translation) almost all the way to the other (most, but not all, of the effect is due to mRNA destabilization).