CHICKEN OVALBUMIN UPSTREAM PROMOTER TRANSCRIPTION FACTORS ACT AS AUXILIARY COFACTORS FOR HEPATOCYTE NUCLEAR FACTOR-4 AND ENHANCE HEPATIC GENE-EXPRESSION

Chicken ovalbumin upstream promoter transcription factors (COUP-TFs) s trongly inhibit transcriptional activation mediated by nuclear hormone receptors, including hepatocyte nuclear factor 4 (HNF-4). COUP-TFs re press HNF-4-dependent gene expression by competition with HNF-4 for co mmon binding sites found in several regulatory regions, Here we show t hat promoters, such as the HNF-1 promoter, which are recognized by HNF -4 but not by COUP-TFs are activated by COUP-TFI and COUP-TFII in conj unction with HNF-4 more than 100-fold above basal levels, as opposed t o about 8-fold activation by HNF-4 alone, This enhancement was strictl y dependent on an intact HNF-4 E domain, In vitro and in vivo evidence suggests that COUP-TFs enhance HNF-4 activity by a mechanism that inv olves their physical interaction with the amino acid 227 to 271 region of HNF-4. Our results indicate that in certain promoters, COUP-TFs ac t as auxiliary cofactors for HNF-4, orienting the HNF-4 activation dom ain in a more efficient configuration to achieve enhanced transcriptio nal activity, These findings provide new insights into the regulatory functions of COUP-TFs, suggesting their involvement in the initial act ivation and subsequent high-level expression of hepatic regulators, as well as in the positive and negative modulation of downstream target genes.