Chromatin: the final frontier in splicing regulation?

Abstract

Pre-mRNA splicing, once thought to be a strictly posttranscriptional event in gene expression, is subject to a multitiered network of regulation. Luco et al. now report in Science that this regulation seems to begin with chromatin modifications, suggesting that the histone code may be a prequel to the splicing code.

Figure 1.. A Potential Model for Chromatin Influence on Alternative Splicing of the FGFR2 Gene

In human mesenchymal cells (hMSCs), the H3K36me3 mark recruits MGR15, which attracts PTB binding at intronic splicing silencer elements near exon IIIb, resulting in IIIb exclusion. Attenuation of this cascade of events by depletion of a H3K36 methyltransferase or MGR15 may derepress IIIb, allowing it to interfere or compete with IIIc inclusion. In epithelial cells, tissue-specific splicing regulators such as ESRPs act to promote IIIb inclusion. Overexpression of the H3K36 methyltransferase or MRG15 may enhance PTB binding, which antagonizes the effect of ESRPs and results in IIIb suppression.