Essential roles of the bHLH transcription factor Hrt2 in repression of atrial gene expression and maintenance of postnatal cardiac function.
The basic helix-loop-helix transcriptional repressor Hairy-related transcription factor 2 (Hrt2) is expressed in ventricular, but not atrial, cardiomyocytes, and in endothelial and vascular smooth muscle cells. Mice homozygous for a null mutation of Hrt2 die perinatally from a spectrum of cardiac abnormalities, raising questions about the specific functions of this transcriptional regulator in individual cardiac cell lineages. Using a conditional Hrt2 null allele, we show that cardiomyocyte-specific deletion of Hrt2 in mice results in ectopic activation of atrial genes in ventricular myocardium with an associated impairment of cardiac contractility and a unique distortion in morphology of the right ventricular chamber. Consistent with the atrialization of ventricular gene expression in Hrt2 mutant mice, forced expression of Hrt2 in atrial cardiomyocytes is sufficient to repress atrial cardiac genes. These findings reveal a ventricular myocardial cell-autonomous function for Hrt2 in the suppression of atrial cell identity and the maintenance of postnatal cardiac function.
Xin
Mei
M
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Small
Eric M
EM
van Rooij
Eva
E
Qi
Xiaoxia
X
Richardson
James A
JA
Srivastava
Deepak
D
Nakagawa
Osamu
O
Olson
Eric N
EN
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006321:Heart / Q000196:embryology; D006325:Heart Atria / Q000378:metabolism*; D006345:Heart Septal Defects, Ventricular / Q000209:etiology; D051379:Mice; D009200:Myocardial Contraction; D051381:Rats; D051880:Receptors, Notch / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics
D009320:Atrial Natriuretic Factor; D051792:Basic Helix-Loop-Helix Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; C485778:Hey2 protein, mouse; C103172:T-box transcription factor 5