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MUCOSAL BIOLOGY

HNF-1 and endodermal transcription factors cooperatively activate Fabpl: MODY3 mutations abrogate cooperativity

¹Division of Biology and Biomedical Sciences and ²Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110

Submitted 14 February 2003 ; accepted in final form 11 March 2003

Hepatocyte nuclear factor (HNF)-1 plays a central role in intestinal and hepatic gene regulation and is required for hepatic expression of the liver fatty acid binding protein gene (Fabpl). An Fabpl transgene was directly activated through cognate sites by HNF-1 and HNF-1, as well as five other endodermal factors: CDX-1, C/EBP, GATA-4, FoxA2, and HNF-4. HNF-1 activated the Fabpl transgene by as much as 60-fold greater in the presence of the other five endodermal factors than in their absence, accounting for up to one-half the total transgene activation by the group of six factors. This degree of synergistic interaction suggests that multifactor cooperativity is a critical determinant of endodermal gene activation by HNF-1. Mutations in HNF-1 that result in maturity onset diabetes of the young (MODY3) provide evidence for the in vivo significance of these synergistic interactions. An R131Q HNF-1 MODY3 mutant exhibits complete loss of synergistic activation in concert with the other endodermal transcription factors despite wild-type transactivation ability in their absence. Furthermore, whereas wild-type HNF-1 exhibited pairwise cooperative synergy with each of the other five factors, the R131Q mutant could synergize only with GATA-4 and C/EBP. Selective loss of synergy with other endodermal transcription factors accompanied by retention of native transactivation ability in an HNF-1 MODY mutant suggests in vivo significance for cooperative synergy.

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