Role of Antisense RNA in Coordinating Cardiac Myosin Heavy Chain Gene Switching

A novel mechanism of regulation of cardiac α and β myosin heavy chain gene by naturally occurring antisense transcription was elucidated via pre-mRNA analysis. Herein, we report the expression of an antisense β myosin heavy chain RNA in the normal rodent myocardium. The pattern of expression of the antisense βMHC RNA (β RNA) under altered thyroid state and in diabetes directly correlates with that of the α pre-mRNA/mRNA, whereas it negatively correlates with the β mRNA expression. Rapid amplification of the 5′ end shows that this antisense transcript originates 2 kb downstream of the β gene, and it is transcribed across the entire β gene from the opposite strand. Our results demonstrate that the β-α myosin heavy chain intergenic DNA possesses a bidirectional transcriptional activity, one direction transcribing the α gene, and the opposite direction transcribing the antisense β RNA. This process turns on the α expression, and it simultaneously turns off that of the β and thus coordinates α and β expression in an opposite fashion. Comparative analyses of the intergenic DNA sequence across five mammalian species revealed a conserved region that is proposed to be a common regulatory region for the α and antisense β promoter. This finding unravels the mechanism of cardiac α-β gene switching and implicates the role of cardiac myosin gene organization with their function.