Uncoupling of Expression of an Intronic MicroRNA and Its Myosin Host Gene by Exon Skipping

Abstract

The ancient MYH7b gene, expressed in striated muscle and brain, encodes a sarcomeric myosin and the intronic microRNA miR-499. We find that skipping of an exon introduces a premature termination codon in the transcript that downregulates MYH7b protein production without affecting microRNA expression. Among other genes, endogenous miR-499 targets the 3′ untranslated region of the transcription factor Sox6, which in turn acts as a repressor of MYH7b transcriptional activity. Thus, concerted transcription and alternative splicing uncouple the level of expression of MYH7b and miR-499 when their coexpression is not required.

This work was supported by NIH grants GM029090 and HL050560 (to L.A.L.).

We thank Daniel Resnicow for his contribution to the identification of MYH7b cDNAs that were missing exon 7, Thomas Armel for his assistance in protein purification, Tom Cheung for PRI algorithm analysis, and Lauren Kiemele of the University of Colorado Cancer Center Proteomics Core for mass spectrometry work. We also thank Tom Blumenthal and Michael Yarus for their critical reading of the manuscript and helpful discussions.