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J Biol Chem, Vol. 274, Issue 53, 38004-38016, December 31, 1999

The Human and Mouse GATA-6 Genes Utilize Two Promoters and Two Initiation Codons^*

Alison Brewer, Christopher Gove^§, Andy Davies^¶, Claire McNulty^§, Dalna Barrow, Manoussos Koutsourakis, Farzin Farzaneh, John Pizzey^§, Adrian Bomford^¶, and Roger Patient^§**

From the  Department of Molecular Medicine, The Rayne Institute, GKT, 123 Coldharbour Lane, London SE5 9NU, United Kingdom, the ^§ Developmental Biology Research Centre, The Randall Institute, Kings College London, 26-29 Drury Lane, London WC2B 5RL, United Kingdom, ^¶ Institute of Liver Studies, GKT, Bessemer Rd., London SE5 9PJ, United Kingdom, and  Erasmus University, Medical Genetics Centre, Department of Cell Biology and Genetics, 3000 DR Rotterdam, The Netherlands

GATA-6 has been implicated in the regulation of myocardial differentiation during cardiogenesis. To determine how its expression is controlled, we have characterized the human and mouse genes. We have mapped their transcriptional start sites and demonstrate that two alternative promoters and 5' noncoding exons are utilized. Both transcript isoforms are expressed in the same tissue-specific and developmental stage-specific pattern, and their ratio appears similar wherever examined. The more upstream noncoding exon showed a substantial degree of homology between the two mammalian species, suggesting a conserved regulatory function. Moreover, in transfection assays we show that elements within this exon act to promote its transcription. Positive regulatory elements that effect transcription from the more downstream exon were not apparent in this assay, revealing a regulatory distinction between the two promoters. We also demonstrate alternative initiator codon usage in both the human and mouse GATA-6 genes. Both isoforms of the protein are synthesized in vitro regardless of which 5' noncoding exon is present in the RNA, although the larger protein has greater transcriptional activation potential in transfection assays. Thus, GATA-6 function in the cell is controlled by a complex interplay of transcriptional and translational regulation.

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^* This work was supported by the British Heart Foundation and by studentships from King's College London (to C. M.) and from Joint Research Committee, King's Healthcare/King's College School of Medicine and Dentistry (to A. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AJ243146 and AJ245649.

^** To whom correspondence should be addressed. Present address: Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH. E-mail: roger.patient@nottingham.ac.uk.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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