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Molecular and Cellular Biology, June 1999, p. 4355-4365, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cooperative Interaction between GATA-4 and GATA-6 Regulates Myocardial Gene Expression

Frédéric Charron,1,2 Pierre Paradis,1 Odile Bronchain,1,2 Georges Nemer,1,3 and Mona Nemer1,2,3,*

Laboratoire de Développement et Différenciation Cardiaques, Institut de Recherches Cliniques de Montréal,1 Department of Medicine, Division of Experimental Medicine, McGill University,2 and Département de Pharmacologie, Université de Montréal,3 Montréal, Québec, Canada

Received 11 December 1998/Returned for modification 12 February 1999/Accepted 10 March 1999

Two members of the GATA family of transcription factors, GATA-4 and GATA-6, are expressed in the developing and postnatal myocardium and are equally potent transactivators of several cardiac promoters. However, several in vitro and in vivo lines of evidence suggest distinct roles for the two factors in the heart. Since identification of the endogenous downstream targets of GATA factors would greatly help to elucidate their exact functions, we have developed an adenovirus-mediated antisense strategy to specifically inhibit GATA-4 and GATA-6 protein production in postnatal cardiomyocytes. Expression of several endogenous cardiac genes was significantly down-regulated in cells lacking GATA-4 or GATA-6, indicating that these factors are required for the maintenance of the cardiac genetic program. Interestingly, transcription of some genes like the alpha - and beta -myosin heavy-chain (alpha - and beta -MHC) genes was preferentially regulated by GATA-4 due, in part, to higher affinity of GATA-4 for their promoter GATA element. However, transcription of several other genes, including the atrial natriuretic factor and B-type natriuretic peptide (ANF and BNP) genes, was similarly down-regulated in cardiomyocytes lacking one or both GATA factors, suggesting that GATA-4 and GATA-6 could act through the same transcriptional pathway. Consistent with this, GATA-4 and GATA-6 were found to colocalize in postnatal cardiomyocytes and to interact functionally and physically to provide cooperative activation of the ANF and BNP promoters. The results identify for the first time bona fide in vivo targets for GATA-4 and GATA-6 in the myocardium. The data also show that GATA factors act in concert to regulate distinct subsets of genes, suggesting that combinatorial interactions among GATA factors may differentially control various cellular processes.

* Corresponding author. Mailing address: Institut de Recherches Cliniques de Montréal, Laboratoire de Développement et Différenciation Cardiaques, 110, des Pins Ouest, Montréal, Québec, Canada H2W 1R7. Phone: (514) 987-5680. Fax: (514) 987-5575. E-mail: nemerm{at}ircm.qc.ca.

Molecular and Cellular Biology, June 1999, p. 4355-4365, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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