One of the things that is an open book is the true scope and physiological relevance of alternative polyadenylation. A recent report in PNAS stirs this pot a bit (even if it leaves things still very much up in the air). Briefly, this group has analyzed various large-scale gene expression repositories – ESTs, SAGE, and microarray – and found a tantalizing possible progression of 3′-UTR length during development. Specifically, it seems as if global (or average) 3′-UTR length increases during the course of embryogenesis. This change in the length of 3′-UTRs seems to be due to differential poly(A) site choice. As I said, very tantalizing.
The abstract and brief commentary follows after the fold.
The 3′ untranslated regions (3′ UTRs) of mRNAs contain cis-acting elements for posttranscriptional regulation of gene expression. Here, we report that mouse genes tend to express mRNAs with longer 3′ UTRs as embryonic development progresses. This global regulation is controlled by alternative polyadenylation and coordinates with initiation of organogenesis and aspects of embryonic development, including morphogenesis, differentiation, and proliferation. Using myogenesis of C2C12 myoblast cells as a model, we recapitulated this process in vitro and found that 3′ UTR lengthening is likely caused by weakening of mRNA polyadenylation activity. Because alternative 3′ UTR sequences are typically longer and have higher AU content than constitutive ones, our results suggest that lengthening of 3′ UTR can significantly augment posttranscriptional control of gene expression during embryonic development, such as microRNA-mediated regulation.
There is a lot of speculation, much of it unfounded, in this study. Moreover, there are problems with each of the sorts of data used in this meta-analysis. EST databases are not very well-suited for analyzing differential gene expression (in my opinion, at least). SAGE data are better, but the execution of the SAGE experiment inherently introduces ambiguity as to the exact position of a poly(A) site. Microarray data are limited by the positions of the probes (along the respective genes) that are used on chips. What is encouraging about this study is that the three datasets seem to agree to a good extent. There is enough here to warrant some more specialized and dedicated experimentation. But I think the conclusions as they stand should be considered as tentative.
The citation:
Ji Z, Lee JY, Pan Z, Jiang B, Tian B. 2009. Progressive lengthening of 3′ untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development. PNAS 106: 7028-7033.
The RNA Underworld 