Interaction of a positive regulatory factor(s) with a 106-base pair upstream region controls transcription of metallothionein-I gene in the liver.

The differential transcription of the cloned mouse metallothionein-I (MT-I) gene in tissues was studied in unfractionated and fractionated nuclear extracts from rat liver and brain. MT-I gene transcription was 10-fold greater in liver nuclear extract than in brain nuclear extract, whereas the level of transcription of the histone H4 gene was almost identical in both tissue extracts. 5' Deletion analysis of upstream sequences revealed that a 106-base pair (bp) region located between the -148- and -42-bp positions with respect to the transcription start site was responsible for the higher level of expression of the MT-I gene in the liver. Preincubation of the liver extract with the 106-bp fragment resulted in a significant decrease in MT-I gene transcription in the liver extract. In contrast, MT-I gene transcription in the brain nuclear extract was not altered by preincubation with the 106-bp upstream sequence. Mixing liver and brain extract did not diminish MT-I gene transcription normally occurring in liver nuclear extract. Preincubation of brain nuclear extract with the MT-I gene had no inhibitory effect on transcription of MT-I gene in liver nuclear extract. These studies suggest that neither an inhibitor nor a negative trans-acting factor in the brain is responsible for the differential transcription of MT-I gene; rather a positive regulatory factor(s) in the liver which interacts with the 106-bp upstream region contributes to the higher level of MT-I gene expression in this tissue.