Extinction of alpha1-antitrypsin expression in cell hybrids is independent of HNF1alpha and HNF4 and involves both promoter and internal DNA sequences.

Abstract	In rat hepatoma x fibroblast somatic cell hybrids, extinction of rat alpha1-antitrypsin (alpha1AT) gene expression is accompanied by the loss of liver-enriched transcription factors hepatocyte nuclear factor 1 (HNF1alpha) and hepatocyte nuclear factor 4 (HNF4). Previous analysis showed that forced expression of functional HNF1alpha failed to prevent extinction of the rat alpha1AT locus in cell hybrids. Here I show that ectopic co-expression of HNF1alpha plus HNF4 fails to prevent extinction of either rat or human alpha1AT genes in cell hybrids. A 40 kb human alpha1AT minilocus integrated into the rat genome is fully silenced in cell hybrids in the presence of transacting factors. The integrated alpha1AT promoter, but not a viral or ubiquitously active promoter, is repressed 35-fold in the cell hybrids. In addition, position effects also contributed to extinction of many integrated transgenes in a cell type-dependent manner. Finally, internal DNA sequences within the human alpha1AT gene contributed dramatically to the extinction phenotype, resulting in a further 10- to 30-fold reduction in alpha1AT gene expression in cell hybrids. Thus, multiple mechanisms contribute to silencing of tissue-specific gene expression of the alpha1AT gene in cell hybrids.
Authors	G A Bulla
Journal	Nucleic acids research (Nucleic Acids Res) Vol. 27 Issue 4 Pg. 1190-7 (Feb 15 1999) ISSN: 0305-1048 [Print] England
PMID	9927755 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors DNA-Binding Proteins HNF1A protein, human HNF1B protein, human Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factor 4 Hnf1a protein, rat MLX protein, human Nuclear Proteins Phosphoproteins Transcription Factors alpha 1-Antitrypsin Hepatocyte Nuclear Factor 1 Hepatocyte Nuclear Factor 1-beta DNA
Topics	Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Cell Line DNA DNA-Binding Proteins Gene Expression Regulation Hepatocyte Nuclear Factor 1 Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factor 1-beta Hepatocyte Nuclear Factor 4 Humans Hybrid Cells Nuclear Proteins Phosphoproteins (genetics, metabolism) Promoter Regions, Genetic Rats Transcription Factors (genetics, metabolism) Tumor Cells, Cultured alpha 1-Antitrypsin (genetics)

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