A different combination of transcription factors modulates the expression of the human transferrin promoter in liver and Sertoli cells.

We have previously identified the functional regions involved in the regulation of human transferrin (Tf) gene expression in the liver and in Sertoli cells of the testis. Here, we show that a different cellular distribution of transcription factors, interacting with the same proximal promoter regions (PRI and PRII), modulates cell type-specific transcription. In the liver, hepatocyte nuclear factor 4 (HNF-4) and the chicken ovalbumin upstream promoter transcription factor (COUP-TF) act at the PRI site, while CCAAT/enhancer-binding proteins (C/EBPs) act at the PRII site. In the testis, distinct combinations of Sertoli proteins SP-A and SP-D and COUP-TF bind to the PRI site, while SP-alpha and SP-beta bind to the PRII site. Cotransfection experiments in Hep3B cells revealed that mostly HNF-4, C/EBP-alpha, C/EBP-delta, and, to a lesser extent, COUP-TF stimulated transcription driven by the -125/+39 region. In Sertoli cells, HNF-4 and COUP-TF appeared to repress, while the C/EBP factors were able to stimulate transcription driven by the -100/+39 region. However, the specific activating combination remains to be defined among the Sertoli proteins. In the non-Tf-expressing HeLa cells, the Tf promoter could be activated by C/EBP-delta. Our data revealed functional antagonism between HNF-4 and COUP-TF, binding to PRI, as well as cross-coupling interactions between HNF-4 and C/EBP, binding to adjacent sites. Thus, cell type-specific DNA-protein interactions, together with protein-protein interactions, may explain the transcriptional regulation of the Tf gene in different cell types.