Alex Palazzo is an Assistant Professor in the Department of Biochemistry at The University of Toronto.
Wow! One of the biggest findings of the year! I'll have to read the article more carefully before I comment on it - previously, I wrote a post on the paper that led to this new discovery that was just published online in Science.
Switching from Repression to Activation: MicroRNAs Can Up-Regulate Translation.
Vasudevan S, Tong Y, Steitz JA.
AU-rich elements (AREs) and microRNA target sites are conserved sequences in mRNA 3'-untranslated regions (3'UTRs) that post-transcriptionally control gene expression. Upon cell-cycle arrest, the ARE in tumor necrosis factor-alpha (TNFalpha) mRNA is transformed into a translation activation signal, recruiting microRNP-associated factors Argonaute (AGO) and fragile-X-mental-retardation-related protein 1 (FXR1). We show that human microRNA miR369-3 directs association of these proteins with the ARE to activate translation. Furthermore, we document that two well-studied microRNAs-Let-7 and the synthetic microRNA cxcr4-likewise induce translation up-regulation of target mRNAs upon cell-cycle arrest; yet, they repress translation in proliferating cells. Thus, activation is a common function of microRNPs upon cell-cycle arrest. We propose that translation regulation by microRNPs oscillates between repression and activation during the cell cycle.
Life Science
Comments
One of my colleagues is sketched out by their conclusions -- specifically, that this is general to all miRNA function.
It's a very bold statement, to say the least. miRNAs are supposed to help regulate cell fate (among other things). When people have seen a miRNA target brain proteins, for example, everybody has assumed that the miRNA is DOWN-regulating those proteins. According to this paper, the opposite would have to be true, unless the miRNA is in a non-brain cell that divides a lot. I'm sure people have published about miRNAs and the tissues they are expressed in. Comparing that to targets should give some quick evidence as to whether this is general.
Posted by: OneRandomScientist | December 1, 2007 8:43 PM
I'm not that surprised... Jopling et al found that a virus was using a human miRNA to increase its expression, and I know I saw some other reference to up-regulating miRNAs at least a year ago. The elucidation of a mechanism and the apparent generality are big news, though. Thanks for bringing this up! (my queue of Science issues to peruse has been growing).
Posted by: dileffante | December 1, 2007 9:10 PM
Well what the hell do you know. I did a quick computational analysis of the tissue expression of the targets of miR-134, which is expressed in the brain, to verify Steitz's hypothesis. I figured that a miRNA expressed in the brain should have targets that are highly expressed in the brain as well if Steitz is correct. And the data support Steitz!
And fyi, your Science link is to Harvard's gateway, which is locked off for most of us :)
Posted by: OneRandomScientist | December 2, 2007 12:31 AM
I fixed the link.
Thanks for doing that bit of bioinformatics. If it turns out to be true, this finding (as you point out) just flipped the whole field on its head.
Posted by: apalazzo | December 2, 2007 9:11 AM
My understanding is that the whole idea of the paper is that the microRNA targets are translationally upregulated in non-dividing (or at least serum starved cells). Therefore analyzing microarray data (transcriptional upregulation) isn't going to tell you much.
Also the example of Jopling et al is maybe not that applicable since the microRNA (mir122) is actually interacting with the 5'UTR of the viral genome and not with the 3'UTR as would be the case in an endogenous mRNA. It's likely a very different mechanism.
Generally I think the paper is sketchy. It's all exogenous RNA they are adding to serum starved cells. What about the effect of endogenous microRNAs?. But the tethering stuff they do is interesting, and there definitely is something going on there.
In any case great post on a truly interesting paper.
Posted by: rob | December 5, 2007 5:43 PM