Regulation of a transcription factor network required for differentiation and metabolism

Hepatocyte nuclear factors (HNFs) are a heterogeneous class of evolutionarily conserved transcription factors that are required for cellular differentiation and metabolism. Mutations in HNF-1 alpha and HNF-4 alpha genes impair insulin secretion and cause type 2 diabetes. Regulation of HNF-4/HNF-1 expression by HNF-3 alpha and HNF-3 beta was studied in embryoid bodies in which one or both HNF-3 alpha or HNF-3 beta alleles were inactivated. HNF-3 beta positively regulated the expression of HNF-4 alpha/HNF-1 alpha and their downstream targets, implicating a role in diabetes. HNF-3 beta was also necessary for expression of HNF-3 alpha. In contrast, HNF-3 alpha acts as a negative regulator of HNF-4 alpha/HNF-1 alpha demonstrating that HNF-3 alpha. and HNF-3 beta have antagonistic transcriptional regulatory functions in vivo. HNF-3 alpha does not appear to act as a classic biochemical repressor but rather exerts its negative effect by competing for HNF-3 binding sites with the more efficient activator HNF-3 beta. In addition, the HNF-3 alpha/HNF-3 beta ratio is modulated by the presence of insulin, providing evidence that the HNF network may have important roles in mediating the action of insulin.