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Am J Physiol Gastrointest Liver Physiol 287: G899-G909, 2004. First published June 3, 2004; doi:10.1152/ajpgi.00150.2004
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MUCOSAL BIOLOGY

Complex regulation of the lactase-phlorizin hydrolase promoter by GATA-4

Herbert M. van Wering,1 Tjalling Bosse,2 Anna Musters,2 Evelien de Jong,1 Naomi de Jong,2 Caroline E. Hogen Esch,3 Francois Boudreau,4 Gary P. Swain,5 Lauren N. Dowling,6 Robert K. Montgomery,6,7 Richard J. Grand,6,7 and Stephen D. Krasinski6,7,8

1Department of Medicine, Free University of Amsterdam, Amsterdam 1081HV; 2Department of Medicine, University of Amsterdam, Amsterdam 1100DD; and 3Department of Medicine, Leiden University, Leiden, The Netherlands 2300RC; 4Departement d'Anatomie et Biologie Cellulaire, Faculte de Medecine, Universite de Sherbrooke, Quebec J1H 5N4, Canada; 5Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; 6Division of Gastroenterology and Nutrition, Department of Medicine, Children's Hospital, Boston 02115; 7Department of Pediatrics, Harvard Medical School, Boston 02115; and 8Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, 02111

Submitted 5 April 2004 ; accepted in final form 28 May 2004

Lactase-phlorizin hydrolase (LPH), a marker of intestinal differentiation, is expressed in absorptive enterocytes on small intestinal villi in a tightly regulated pattern along the proximal-distal axis. The LPH promoter contains binding sites that mediate activation by members of the GATA-4, -5, and -6 subfamily, but little is known about their individual contribution to LPH regulation in vivo. Here, we show that GATA-4 is the principal GATA factor from adult mouse intestinal epithelial cells that binds to the mouse LPH promoter, and its expression is highly correlated with that of LPH mRNA in jejunum and ileum. GATA-4 cooperates with hepatocyte nuclear factor (HNF)-1{alpha} to synergistically activate the LPH promoter by a mechanism identical to that previously characterized for GATA-5/HNF-1{alpha}, requiring physical association between GATA-4 and HNF-1{alpha} and intact HNF-1 binding sites on the LPH promoter. GATA-4 also activates the LPH promoter independently of HNF-1{alpha}, in contrast to GATA-5, which is unable to activate the LPH promoter in the absence of HNF-1{alpha}. GATA-4-specific activation requires intact GATA binding sites on the LPH promoter and was mapped by domain-swapping experiments to the zinc finger and basic regions. However, the difference in the capacity between GATA-4 and GATA-5 to activate the LPH promoter was not due to a difference in affinity for binding to GATA binding sites on the LPH promoter. These data indicate that GATA-4 is a key regulator of LPH gene expression that may function through an evolutionarily conserved mechanism involving cooperativity with an HNF-1{alpha} and/or a GATA-specific pathway independent of HNF-1{alpha}.

lactase-phlorizin hydrolase; intestinal differentiation; GATA-4; hepatocyte nuclear factor-1{alpha}


Address for reprint requests and other correspondence: S. D. Krasinski, GI/Cell Biology, EN 1220, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115 (E-mail: stephen.krasinski{at}childrens.harvard.edu)




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