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activates liver fatty acid binding protein gene cooperatively with endodermal transcription factors: MODY3 mutations selectively abrogate cooperativity
1 Department of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
2 Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
* To whom correspondence should be addressed. E-mail: simon_t{at}kids.wustl.edu.
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 is 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 up to sixty-fold greater in the presence the other five endodermal factors than in their absence, accounting for up to half the total transgene activation by the group of six factors. This degree of synergistic interaction suggests that multi-factor 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, while 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 the in vivo significance of cooperative synergy.
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