A MyoD1-independent muscle-specific enhancer controls the expression of the beta-myosin heavy chain gene in skeletal and cardiac muscle cells.
The beta-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 beta-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 beta-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 beta-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 beta-MHC promoter. Thus, MyoD and MyoD-related processes are neither required nor sufficient for the expression of the beta-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.
Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital, Boston, Massachusetts.
W R
WR
Thompson
B
B
Nadal-Ginard
V
V
Mahdavi
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D005796:Genes; D005822:Genetic Vectors; D006367:HeLa Cells; D006321:Heart / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009132:Muscles / Q000502:physiology*; D017570:MyoD Protein; D009218:Myosins / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism*; D009710:Nucleotide Mapping; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection
D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D009218:Myosins