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

Abstract

Hepatocyte nuclear factor (HNF)-1α 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-1α and HNF-1β, as well as five other endodermal factors: CDX-1, C/EBPβ, GATA-4, FoxA2, and HNF-4α. HNF-1α 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-1α. Mutations in HNF-1α that result in maturity onset diabetes of the young (MODY3) provide evidence for the in vivo significance of these synergistic interactions. An R131Q HNF-1α 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-1α exhibited pairwise cooperative synergy with each of the other five factors, the R131Q mutant could synergize only with GATA-4 and C/EBPβ. Selective loss of synergy with other endodermal transcription factors accompanied by retention of native transactivation ability in an HNF-1α MODY mutant suggests in vivo significance for cooperative synergy.