An intronic silencer element is responsible for specific zonal expression of glutamine synthetase in the rat liver†

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Abstract
The most striking phenomenon of glutamine synthetase (GS) expression in the liver is its unique restriction to cells surrounding the terminal hepatic venules. Expression is positively regulated by elements located in the 5′‐upstream region and in the first intron of the gene. It was long believed that transcription factors present in GS‐positive cells and absent in GS‐negative cells are responsible for the phenomenon of zonal expression. However, strong enhancers are equally active in both types of cells. Therefore, the existence of a silencer mechanism in GS‐negative hepatocytes was postulated. In the present study, a GS silencer element was investigated that was previously identified within the first intron and was shown to be able to prevent glucocorticoid‐induced expression in cells negative for a transacting factor designated GS silencer element–binding protein. Reporter gene assays with the silencer element in combination with the most potent 5′‐enhancer of the GS gene demonstrate that the silencer element is able to prevent enhancement mediated by the 5′‐enhancer in combination with a heterologous as well as with the homologous promoter. More importantly, the effect of the silencer is shown to be restricted to GS‐negative hepatocytes. In conclusion, the phenomenon of zonal expression of GS in the liver is caused by a protein present in GS‐negative cells and absent in GS‐positive cells that interacts with the silencer element in the first intron and not by a differential expression of enhancer‐binding proteins. (HEPATOLOGY 2005.)