HNF-1 alpha and HNF-1 beta (vHNF-1) share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro

Abstract

HNF-1 alpha (previously referred to as HNF-1, LPB1, and APF) is a vertebrate transcription factor that contains a divergent homeo domain and plays a prominent role in regulating genes that have the common characteristic of being expressed in hepatocytes and a complex group of endodermally and mesodermally derived tissues. HNF-1 alpha is unique among the vertebrate homeo domain-containing proteins in that it dimerizes in the absence of its DNA recognition sequence, suggesting the possibility that the function of HNF-1 alpha may be diversified by forming heterodimers with other related proteins. We report the initial characterization of HNF-1 beta, which is closely related to HNF-1 alpha and is able to form heterodimers with HNF-1 alpha in vitro. Although HNF-1 alpha, but not HNF-1 beta, is expressed in the liver, HNF-1 alpha and HNF-1 beta are coexpressed in the murine Hepa1A cell line and in the mammalian kidney where a subset of hepatocyte genes are expressed. In contrast, exclusive expression of HNF-1 beta is associated with repression of a subset of hepatocyte-specific genes in the dedifferentiated hepatocyte cell line C2, differentiated F9 cells, in somatic hybrids between hepatocytes and fibroblasts, and in the lung. The extent of heterodimerization may be regulated in a tissue-specific way because freely exchangeable heterodimers are formed in Jurkat T cells transfected with HNF-1 alpha and HNF-1 beta, whereas in liver cells stable homodimers are present. These studies define a pair of homeo domain proteins that have the potential to interact to produce an embryologically complex pattern of gene expression.