Global regulation of alternative splicing: starting with Nova

The global analysis of alternative splicing is complicated by the fact that standard microarrays, and even tiling arrays without junction oligos, do a poor job of reporting on the ratio between alternatively spliced mRNA isoforms that share most of their nucleotides. Only in the past few years has alternative splicing data from arrays been reported (see Clark et al., 2002; Johnson et al., 2003; Stolc et al. 2004 and Pan et al. 2004). It was therefore exciting to see the paper by Ule et al. in the new issue of Nature Genetics reporting the effect of Nova2 knockouts on global patterns of alternative splicing in the mouse brain.

A custom microarray from Affymetrix was used for this study. Although I applaud the efforts of Hui Wang and John Blume to bring alternative splicing to the Affymetrix platform (and [full disclosure] I own some Affymetrix stock), custom chips are extremely expensive. I have my eyes on the Agilent platform used by Pan et al. and what I would really like to see is the widespread use of a common (inexpensive) platform so that publicly available data can be mined for unexpected associations.

Another notable aspect of this study is the truly remarkable degree of functional connection between proteins whose isoforms appear to be regulated by Nova2. Figure 5 in this paper makes a compelling case for the idea that while transcriptional regulators can turn gene sets on and off, splicing regulators can fine-tune an entire module for a specific task.

Finally, it is important to note that these experiments are facilitated by the fact that Nova2 knockout mice are viable, which rendered tissue-specific ablation (as practiced by Ding et al. and Xu et al. for similar studies on SR proteins) unnecessary. That is why we consider it a good thing that so many of the Arabidopsis SR proteins we work with are not essential. This does not mean they are not important!