Retinoid X receptor alpha represses GATA-4-mediated transcription via a retinoid-dependent interaction with the cardiac-enriched repressor FOG-2.
Dietary vitamin A and its derivatives, retinoids, regulate cardiac growth and development. To delineate mechanisms involved in retinoid-mediated control of cardiac gene expression, the regulatory effects of the retinoid X receptor alpha (RXR alpha) on atrial naturietic factor (ANF) gene transcription was investigated. The transcriptional activity of an ANF promoter-reporter in rat neonatal ventricular myocytes was repressed by RXR alpha in the presence of 9-cis-RA and by the constitutively active mutant RXR alpha F318A indicating that liganded RXR confers the regulatory effect. The RXR alpha-mediated repression mapped to the proximal 147 bp of the rat ANF promoter, a region lacking a consensus retinoid response element but containing several known cardiogenic cis elements including a well characterized GATA response element. Glutathione S-transferase "pull-down" assays revealed that RXR alpha interacts directly with GATA-4, in a ligand-independent manner, via the DNA binding domain of RXR alpha and the second zinc finger of GATA-4. Liganded RXR alpha repressed the activity of a heterologous promoter-reporter construct containing GATA-response element recognition sites in cardiac myocytes but not in several other cell types, suggesting that additional cardiac-enriched factors participate in the repression complex. Co-transfection of liganded RXR alpha and the known cardiac-enriched GATA-4 repressor, FOG-2, resulted in additive repression of GATA-4 activity in ventricular myocytes. In addition, RXR alpha was found to bind FOG-2, in a 9-cis-RA-dependent manner. These data reveal a novel mechanism by which retinoids regulate cardiogenic gene expression through direct interaction with GATA-4 and its co-repressor, FOG-2.
Clabby
Martha L
ML
Center for Cardiovascular Research, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Robison
Trevor A
TA
Quigley
Heather F
HF
Wilson
David B
DB
Kelly
Daniel P
DP
D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000235:genetics*; D001665:Binding Sites; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D050991:GATA4 Transcription Factor; D005982:Glutathione Transferase / Q000235:genetics; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology*; D014157:Transcription Factors / Q000494:pharmacology* / Q000502:physiology*; D014158:Transcription, Genetic; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D009320:Atrial Natriuretic Factor; D005982:Glutathione Transferase