A transcriptional hierarchy involved in mammalian cell-type specification

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Abstract
ALTHOUGH transcriptional hierachies have been extensively studied in invertebrates, their involvement in mammalian cell-type specification is poorly understood1,2. 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 extinguished3–6. These results indicated that the homeoprotein hepatocyte nuclear factor-lα (HNF-lα)7–8, and HNF-4, a member of the steroid hormone receptor superfamily9, 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-lα, as deletion of an HNF-4 binding site in the HNF-lα promoter abolished promoter activity, and HNF-4→ potently transactivated the HNF-lα promoter in cotransfection assays. Moreover, genetic complementation of dedifferentiated hepatomas with HNF-4 complementary DNA rescued expression of endogenous HNF-lα messenger RNA and DNA-binding activity. Our studies therefore define an HNF-4→ HNF-1 α (4 -→ 1α) transcriptional hierarchy operative in differentiated hepatocytes but selectively inhibited by an extinguishing locus and somatic mutations which antagonize the liver phenotype.