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1 Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
2 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
3 Childrens Hospital and Program for Developmental and Reproductive Biology, University of Helsinki, Helsinki, Finland
4 Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri, USA
* To whom correspondence should be addressed. E-mail: simon_t{at}kids.wustl.edu.
Transcriptional regulation by GATA-4, GATA-5, and GATA-6 in intestine and liver was
explored utilizing a transgene constructed from the proximal promoter of the rat liver fatty acid
binding protein gene (Fabpl). An immunohistochemical survey detected GATA-4 and GATA-6
in enterocytes, GATA-6 in hepatocytes, and GATA-5 in neither cell type in adult animals. In
cell transfection assays, GATA-4 or GATA-5 but not GATA-6 activated the Fabpl transgene
solely through the most proximal of three GATA binding sites in the Fabpl promoter. However,
all three factors activated transgenes constructed from each Fabpl site upstream of a minimal
viral promoter. GATA factors interact with HNF-1
, and the proximal Fabpl GATA site adjoins
an HNF-1 site. GATA-4, GATA-5, or GATA-6 bound to HNF-1 in solution and all cooperated
with HNF-1 to activate the Fabpl transgene. Mutagenizing all Fabpl GATA sites abrogated
transgene activation by GATA factors, but GATA-4 activated the mutagenized transgene in the
presence of HNF-1. These in vitro results suggested GATA/HNF-1 interactions function in
Fabpl regulation, and in vivo relevance was determined with subsequent experiments. In mice,
the Fabpl transgene was active in enterocytes and hepatocytes, a transgene with mutagenized
HNF-1 site was silent, and a transgene with mutagenized GATA sites had identical expression as
the native transgene. Mice mosaic for biallelic Gata4 inactivation lost intestinal but not hepatic
Fabpl expression in Gata4-deficient cells but not wild-type cells. These results demonstrate
GATA-4 is critical for intestinal gene expression in vivo, and suggest a specific
GATA-4/HNF-1 physical and functional interaction in Fabpl activation.
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