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. Author manuscript; available in PMC: 2014 Mar 29.
Published in final edited form as: Nat Rev Mol Cell Biol. 2012 Jan 23;13(2):115–126. doi: 10.1038/nrm3274

Figure 3. H3K36me3 influences alternative splicing in a cell-type specific manner.

Figure 3

The fibroblast growth factor receptor 2 (FGFR2) locus that undergoes alternative splicing consists of two mutually exclusive exons, IIIb and IIIc, which are located between the constitutive exons 7 and 10. Mesenchymal stem cells favour the inclusion of exon IIIc and achieve this by repressing splicing of exon IIIb. Nucleosomes present near exon IIIb contain the SET domain-containing 2 (SETD2)-dependent trimethylated Lys36 on histone H3 (H3K36me3) ‘mark’ and its reader protein MORF-related gene 15 (MRG15). MRG15 also interacts with polypyrimidine tract-binding protein (PTB), a known repressor of exon inclusion, and this may be the mechanism by which the methylated H3K36 mark can influence splicing at this locus. In epithelial cells, FGFR2 expresses exon IIIb but excludes exon IIIc. Epithelial splicing regulatory protein (ESRP) is expressed and stimulates the inclusion of exon IIIb; reduced levels of H3K36me3 present at this exon, possibly as a result of lower SETD2 levels, allow its derepression. The role of dimethylases, such as the proteins of the nuclear receptor SET domain-containing (NSD) family, in this process has yet to be determined but these enzymes could also influence H3K36 methylation here.