A Hormone-Encoding Gene Identifies a Pathway for Cardiac but Not Skeletal Muscle Gene Transcription

Abstract

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.

The Natriuretic Peptide System: A Single Entity, Pleiotropic Effects

“…BNP storage in atrial granules with ANP is limited. Still, researchers have found high concentrations of this peptide in the cardiac ventricles, where it is not stored and released in the presence of predisposing stimuli, but can be transcribed and then assembled in response to promoting circumstances such as cardiac pressure and volume overload under the control of the transcription factor GATA4 [15].…”

Uncovering the Genetic Basis of Congenital Heart Disease: Recent Advancements and Implications for Clinical Management

“…GATA4 is a mutual cofactor of NKX2.5 ; neither alone is sufficient to initiate cardiogenesis. 22 , 23 , 24 , 25 GATA4 and the related GATA5 and GATA6 are expressed within the developing heart, and variants of GATA genes have been implicated in CHD. 18 GATA4 variants have been associated with ASD, VSD, and TOF.…”

NRSF/REST-Mediated Epigenomic Regulation in the Heart: Transcriptional Control of Natriuretic Peptides and Beyond

“…This human BNP promoter proximal region contains potential GATA, CArG, AP-1/CRE-like and M-CAT elements, which are conserved among humans, mice and rats [ 32 , 34 , 35 , 36 ]. All of these elements have been shown to control the cardiac selectivity of gene expression [ 35 , 36 , 37 , 38 , 39 , 40 ] and to mediate both basal and inducible expression of NPPB [ 35 , 36 , 39 , 40 , 41 ]. Other sites in the distal regions of human NPPB 5′-FR, such as NRSE, NF-AT binding sites, SSREs and TRE, have also been found to play important roles in the inducible activation of the human BNP promoter [ 42 , 43 , 44 , 45 ].…”