A MyoD1-independent muscle-specific enhancer controls the expression of the β-myosin heavy chain gene in skeletal and cardiac muscle cells

The β-cardiac myosin heavy chain is the major contractile protein expressed in two sarcomeric muscles of distinct embryologic origins, the ventricular myocardium and slow twitch skeletal muscle. Characterization of the cis-acting regulatory sequences of the human and the rat β-MHC genes established that their expression in these two muscle types is controlled, at least in part, by common mechanisms involving a muscle-specific enhancer. This enhancer consists of distinct but cooperative subelements that interact with muscle-specific nuclear proteins. In contrast to other muscle-specific enhancers, the β-MHC gene enhancer is unresponsive, directly or indirectly, to the muscle lineage-determining and muscle gene-transactivating helix-loop-helix factors MyoD and myogenin. A MyoD-binding site in the rat β-MHC promoter is not required for transcriptional activity in skeletal and cardiac cells, but is necessary for activation in 10T1/2 and CV1 cells transfected with MyoD. In addition, this element is absent from the human β-MHC promoter. Thus, MyoD and MyoD-related processes are neither required nor sufficient for the expression of the β-MHC gene either in cardiac or skeletal muscle cells. These observations provide evidence for the existence of myogenic regulatory programs that precede and/or differ from those governed by known myogenic helix-loop-helix transactivators.