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1 Department of Medicine, Free University of Amsterdam, Amsterdam, The Netherlands
2 Department of Medicine, University of Amsterdam, Amsterdam, The Netherlands
3 Department of Medicine, Leiden University, Leiden, The Netherlands
4 Departement d'Anatomie et Biologie Cellulaire, Faculte de Medicine, Universite de Sherbrooke, Sherbrooke, Quebec, Canada
5 Divison of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
6 Division of Gastroenterology and Nutrition, Childrens Hospital, Boston, MA, USA
7 Division of Gastroenterology and Nutrition, Childrens Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
8 Division of Gastroenterology and Nutrition, Childrens Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: stephen.krasinski{at}childrens.harvard.edu.
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, -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 HNF-1
to synergistically activate the LPH
promoter by a mechanism identical to that previously characterized for GATA-5/HNF-1, requiring
physical association between GATA-4 and HNF-1, and intact HNF-1 binding sites on the LPH
promoter. GATA-4 also activates the LPH promoter independently of HNF-1, in contrast to
GATA-5, which is unable to activate the LPH promoter in the absence of HNF-1. 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
of GATA-4 and GATA-5 to activate the LPH promoter was not due to a difference in affinity for
binding to the 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 HNF-1 and/or a GATA-specific pathway that is independent of HNF-
1.
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