Regulation of a Transcription Factor Network Required for Differentiation and Metabolism

Abstract

Hepatocyte nuclear factors (HNFs) are a heterogeneous class of evolutionarily conserved transcription factors that are required for cellular differentiation and metabolism. Mutations in HNF-1α and HNF-4α genes impair insulin secretion and cause type 2 diabetes. Regulation of HNF-4/HNF-1 expression by HNF-3α and HNF-3β was studied in embryoid bodies in which one or both HNF-3α or HNF-3β alleles were inactivated. HNF-3β positively regulated the expression of HNF-4α/HNF-1α and their downstream targets, implicating a role in diabetes. HNF-3β was also necessary for expression of HNF-3α . In contrast, HNF-3α acts as a negative regulator of HNF-4α/HNF-1α demonstrating that HNF-3α and HNF-3β have antagonistic transcriptional regulatory functions in vivo. HNF-3α 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-3β . In addition, the HNF-3α/HNF-3β ratio is modulated by the presence of insulin, providing evidence that the HNF network may have important roles in mediating the action of insulin.