Transcriptional Activators in Hepatocytes1

A longstanding quest of developmental biology has been to understand the molecular switches that determine which sets of genes are expressed in selected differentiated cell types. Since regulation of gene expression is predominantly at the level of mRNA synthesis (reviewed in Ref. 1), the problem initially becomes one of defining the protein factors that establish and maintain a gene in a transcriptionally active state within the appropriate cell lineage. In mammalian systems, dissection of gene regulatory pathways using the power of genetic selections to identify regulatory proteins remains a largely elusive goal. Consequently, much of our current knowledge of such processes in complex eukaryotes is derived from biochemical characterization of transcriptional activator proteins, especially those that target specific genes by complexing with defined DNA elements located in the vicinity of the transcription unit (2). The mammalian hepatocyte represents a facile and widely exploited system for the investigation of tissuespecific transcription, owing mainly to the large diversity of genes whose expression is restricted to the liver, but also due to the amenability of liver tissue to biochemical experimentation. Liver gene transcription, as with other tissue-specific genes, depends on regulatory sequences situated close to the mRNA start site (i.e., within several hundred bp2 upstream), as well as those found in more distant locations (so-called enhancers). Both types of elements can contribute to the hepatocyte-restricted properties of gene transcription (see, for example, Refs. 3-8). Thus far, the proximal sequences and their binding proteins have been the more thoroughly investigated, a fact that is reflected in the subject matter for this review. This bias should not be interpreted to indicate that the long-range enhancers are less important than proximal signals in establishing histotypic patterns of gene transcription. The intent of this article is to summarize some of the emergent information on liver-specific transcriptional activator proteins. Due to limitations of space, no attempt has been made to prepare a comprehensive