THE REGULATION OF THE HUMAN BETA-MYOSIN HEAVY-CHAIN GENE

The human myosin heavy-chain (MHC) genes for cardiac and skeletal muscle exist as a multigene family with eight or more non-allelic genes. Two of them code for the cardiac-alpha and beta-myocin HCs. They are located on chromosome 14. The skeletal muscle myosin HC genes are on chromosome 17. The cardiac MHCs coexist in the heart, however, with a distinct distribution within cardiac tissue of the human adult. Alpha-MHC is predominantly found in the atria and beta-MHC is found in the ventricles. Both genes are also expressed in certain types of skeletal muscle fibers. We have sequenced the beta-gene in its entire length and have further studied in detail its expression in muscle cells. Promoter activities were tested using DNA-mediated gene transfer in cultured chicken embryonic myoblasts. By deletion mapping of the 5' flanking region of the beta-gene a candidate signal sequence was identified in a region which stimulates the promoter in a tissue specific and differentiation dependent mode. The presumed signal was located about 210 bp 5' to the basic promoter which, by itself, is almost inactive, even in muscle cells. The sequence of the signal (CAGCTG) has homology to known E-box sequences. E-boxes (consensus sequence CANNTG) constitute a family of transcription control sites frequently found upstream of muscle genes. In nuclear extracts of cardiac and skeletal muscle (of rabbit) a protein was identified which binds to the region containing the E-box like motif of the beta-gene. Since this protein was present in both types of muscle, overlapping expression control patterns are assumed to operate in these tissues.