A C EBP-BINDING SITE IN THE TRANSFERRIN PROMOTER IS ESSENTIAL FOR EXPRESSION IN THE LIVER BUT NOT THE BRAIN OF TRANSGENIC MICE/

The gene for the iron-binding protein transferrin is transcribed at a high level in liver hepatocytes but is also active in several other ce ll types, including oligodendrocytes in the brain. Enhancer elements b etween bp -560 and -44 of the transferrin gene promoter specifically a ctivated transcription from a heterologous promoter in transgenic mous e liver and brain. Within this region, a potent cis-acting element bet ween bp -98 and -83 was found to be essential for gene activity in bot h cultured hepatocytes and transgenic mouse liver. The -98 to -83 elem ent contains a CCAAT sequence and is specifically bound by a nuclear f actor from mouse liver that is homologous to rat liver C/EBP (CAAT enh ancer-binding protein). Point mutations within this binding site inhib it factor binding and abolish transcription in transfected hepatoma ce lls. When placed in the context of the 3,000-bp transferrin promoter, the C/EBP binding site mutation causes a complete loss of transcriptio n in transgenic mouse liver; however, transgene expression in the brai n of the same animals was unaffected. These results suggest a modular structure for the transferrin promoter and demonstrate that deletions or specific point mutations can be used to generate transgene promoter s with an activity more restricted than that of their endogenous count erparts.