A Transcriptional Hierarchy Involved in Mammalian Cell-Type Specification

Nature. 1992 Jan 30;355(6359):457-61. doi: 10.1038/355457a0.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cell Line
  • Chromosome Deletion
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 1-beta
  • Hepatocyte Nuclear Factor 4
  • Liver / physiology*
  • Liver Neoplasms, Experimental
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Nuclear Proteins*
  • Oligodeoxyribonucleotides
  • Organ Specificity
  • Phorbol 12,13-Dibutyrate / pharmacology
  • Phosphoproteins*
  • Promoter Regions, Genetic
  • Restriction Mapping
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Transcription, Genetic* / drug effects
  • Transfection

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 4
  • Hnf1a protein, mouse
  • Hnf1b protein, mouse
  • Nuclear Proteins
  • Oligodeoxyribonucleotides
  • Phosphoproteins
  • Tcfl4 protein, mouse
  • Transcription Factors
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-beta
  • Phorbol 12,13-Dibutyrate