Regulation of myosin heavy chain genes in the heart

Advances in our knowledge of the regulation of cardiac myosin isoforms made possible by molecular cloning of the alpha- and beta-MHCs genes are reviewed. Expression of these genes in heart does not seem to require MyoD or related proteins of the skeletal muscle myogenic program. Cardiac MHC genes are under the control of T3, which stimulates transcription of the alpha-MHC gene and inhibits beta-MHC mRNA production both in vivo and in cultured heart cells. The responsiveness of the genes to T3 varies in different mammals, however. The genes are most responsive in rat and rabbit, intermediate in sensitivity in calf and subhuman primate (baboon), and very resistant in the dog. The human alpha-MHC gene is T3-inducible in ventricle, but the degree of response has not been quantified. Introduction of chimeric plasmids containing 5' flanking sequences of cardiac MHC genes fused to the CAT gene into cultured heart cells and transgenic animals has permitted identification of regulatory elements. Although the genes are closely linked in genomic DNA, they are controlled independently. The element within the alpha-MHC promoter responsible for induction by T3 is located approximately 160 base pairs from the transcription initiation site. Additional transcriptional activators located 5' upstream amplify the response to T3, probably by looping out intervening DNA sequences. The proximal region of the beta-MHC gene contains important regulatory elements, including those required for repression by T3, muscle-specific expression, a MyoD-independent positive element, and a hormone-independent repressor.(ABSTRACT TRUNCATED AT 250 WORDS)