A transcriptional hierarchy involved in mammalian cell-type specification

Abstract

Although transcriptional hierarchies have been extensively studied in invertebrates, their involvement in mammalian cell-type specification is poorly understood. Here we report a hepatocyte transcriptional cascade suggested by the expression patterns of hepatic transcription factors in dedifferentiated hepatomas and hepatocyte: fibroblast hybrids in which the liver phenotype was extinguished. These results indicated that the homeoprotein hepatocyte nuclear factor-1 alpha (HNF-1 alpha), and HNF-4, a member of the steroid hormone receptor superfamily, were regulated coordinately or in a hierarchy by a higher-order locus, independently of other hepatic transactivators. HNF-4 was implicated as an essential positive regulator of HNF-1 alpha, as deletion of an HNF-4 binding site in the HNF-1 alpha promoter abolished promoter activity, and HNF-4 potently transactivated the HNF-1 alpha promoter in cotransfection assays. Moreover, genetic complementation of dedifferentiated hepatomas with HNF-4 complementary DNA rescued expression of endogenous HNF-1 alpha messenger RNA and DNA-binding activity. Our studies therefore define an HNF-4----HNF-1 alpha (4----1 alpha) transcriptional hierarchy operative in differentiated hepatocytes but selectively inhibited by an extinguishing locus and somatic mutations which antagonize the liver phenotype.

Hepatocyte nuclear factor-4α promotes differentiation of intestinal epithelial cells in a coculture system

“…5B). This suggested that HNF-4␣ could directly activate HNF-1␣ gene transcription as reported in hepatocytes (26,36). The expression of several genes linked to differentiation and metabolism and identified to be upregulated during the coculture kinetics ( Fig.…”

“…In addition, HNF-4␣ is able to rapidly induce HNF-1␣ gene transcript and protein levels within the IEC context. This molecular interaction is probably due to a direct transcriptional action of HNF-4␣ on the HNF-1␣ promoter since it was previously reported that HNF-4␣ can directly control the transcription of HNF-1␣ in hepatocytes (26,36). HNF-1␣ was also shown to control HNF-4␣ transcription specifically in pancreatic cells (3), a relationship that was not observed in our culture model system.…”

Transcriptional control of genes that regulate glycolysis and gluconeogenesis in adult liver

“…Moreover, the PEPCK, L pyruvate kinase and aldolase B promoters, which contain a functional HNF-1 site, also bind HNF-3 or HNF-4. Since HNF-3 and HNF-4 stimulate transcription of the HNF-la gene [153], and therefore occupy a higher position in the hierarchy of transcription factors, one could have expected that they need not bind to genes regulated by HNF-1. The fact that they do suggests a functional redundancy or a requirement in vivo for a co-operation between liver-specific factors to promote protein-protein interactions.…”

Adenovirus-mediated Transfer of CCAAT/Enhancer-binding Protein-α Identifies a Dominant Antiproliferative Role for This Isoform in Hepatocytes

“…Finally, in hepatoma cell lines and hepatocytederived hybridomas, loss of C/EBP␣ does not extinguish the hepatocyte phenotype (49,50). Thus, although C/EBP␣ has a clear antiproliferative effect in adipocytes, its role in the liver appears more complex.…”