A hormone-encoding gene identifies a pathway for cardiac but not skeletal muscle gene transcription.
In contrast to skeletal muscle, the mechanisms responsible for activation and maintenance of tissue-specific transcription in cardiac muscle remain poorly understood. A family of hormone-encoding genes is expressed in a highly specific manner in cardiac but not skeletal myocytes. This includes the A- and B-type natriuretic peptide (ANP and BNP) genes, which encode peptide hormones with crucial roles in the regulation of blood volume and pressure. Since these genes are markers of cardiac 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 erythroid but not to muscle-specific promoters and enhancers, including a requirement for regulatory elements containing GATA motifs. A cDNA clone corresponding to a member of the GATA family of transcription factors was isolated from a cardiomyocyte cDNA library. Transcription of this GATA gene is restricted mostly to the heart and is undetectable in skeletal muscle. Within the heart, GATA transcripts are localized in ANP- and BNP-expressing myocytes, and forced expression of the GATA protein in heterologous cells markedly activates transcription from the natural cardiac muscle-specific ANP and BNP promoters. This GATA-dependent pathway defines the first mechanism for cardiac muscle-specific transcription. Moreover, the present findings reveal striking similarities between the mechanisms controlling gene expression in hematopoietic and cardiac cells and may have important implications for studies of cardiogenesis.
Grépin
C
C
Laboratoire de Développement et Différenciation Cardiaques, Institut de Recherches Cliniques de Montréal, Québec, Canada.
Dagnino
L
L
Robitaille
L
L
Haberstroh
L
L
Antakly
T
T
Nemer
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis* / Q000235:genetics; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D016384:Consensus Sequence; D017124:Conserved Sequence; D017931:DNA Primers; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D050991:GATA4 Transcription Factor; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014981:Xenopus; D029867:Xenopus Proteins; D016335:Zinc Fingers
D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; C494751:GATA4 protein, Xenopus; D014157:Transcription Factors; D029867:Xenopus Proteins; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor