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A transcriptional hierarchy involved in mammalian cell-type specification

Nature volume 355, pages 457–461 (1992)Cite this article

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.

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Author notes

  1. Frances M. Sladek and James E. Darnell: Laboratory of Molecular Cell Biology, The Rockefeller University, New York, New York 10021, USA

Authors and Affiliations

  1. Howard Hughes Medical Institute, Unit in Molecular and Genetic Medicine, Stanford University School of Medicine, Stanford, California, 94305-5425, USA

    Calvin J. Kuo, Pamela B. Conley, Lei Chen, Frances M. Sladek, James E. Darnell Jr & Gerald R. Crabtree

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  1. Calvin J. Kuo
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  2. Pamela B. Conley
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  3. Lei Chen
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  4. Frances M. Sladek
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  5. James E. Darnell Jr
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  6. Gerald R. Crabtree
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Kuo, C., Conley, P., Chen, L. et al. A transcriptional hierarchy involved in mammalian cell-type specification. Nature 355, 457–461 (1992). https://doi.org/10.1038/355457a0

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