A HORMONE-ENCODING GENE IDENTIFIES A PATHWAY FOR CARDIAC BUT NOT SKELETAL-MUSCLE GENE-TRANSCRIPTION

In contrast to skeletal muscle, the mechanisms responsible for activat ion and maintenance of tissue-specific transcription in cardiac muscle remain poorly understood. A family of hormone-encoding genes is expre ssed in a highly specific manner in cardiac but not skeletal myocytes. This includes the A- and B-type natriuretic peptide (ANP and BNP) gen es, which encode peptide hormones with crucial roles in the regulation of blood volume and pressure. Since these genes are markers of cardia c cells, we have used them to probe the mechanisms for cardiac muscle- specific transcription. Cloning and functional analysis of the rat BNP upstream sequences revealed unexpected structural resemblance to eryt hroid but not to muscle-specific promoters and enhancers, including a requirement for regulatory elements containing GATA moths. A cDNA clon e corresponding to a member of the GATA family of transcription factor s was isolated from a cardiomyocyte cDNA library. Transcription of thi s GATA gene is restricted mostly to the heart and is undetectable in s keletal muscle. Within the heart, GATA transcripts are localized in AN P- and BNP-expressing myocytes, and forced expression of the GATA prot ein in heterologous cells markedly activates transcription from the na tural cardiac muscle-specific ANP and BNP promoters. This GATA-depende nt pathway defines the first mechanism for cardiac muscle-specific tra nscription. Moreover, the present findings reveal striking similaritie s between the mechanisms controlling gene expression in hematopoietic and cardiac cells and may have important implications for studies of c ardiogenesis.