Negative autoregulation of HNF-4alpha gene expression by HNF-4alpha1.
HNF-4alpha (hepatocyte nuclear factor-4alpha) is required for tissue-specific expression of many of the hepatic, pancreatic, enteric and renal traits. Heterozygous HNF-4alpha mutants are inflicted by MODY-1 (maturity onset diabetes of the young type-1). HNF-4alpha expression is reported here to be negatively autoregulated by HNF-4alpha1 and to be activated by dominant-negative ... HNF-4alpha1. Deletion and chromatin immunoprecipitation analysis indicated that negative autoregulation by HNF-4alpha1 was mediated by its association with the TATA-less HNF-4alpha core promoter enriched in Sp1, but lacking DR-1 response elements. Also, negative autoregulation by HNF-4alpha1 was independent of its transactivation function, being similarly exerted by transcriptional-defective MODY-1 missense mutants of HNF-4alpha1, or under conditions of suppressing or enhancing HNF-4alpha activity by small heterodimer partner or by inhibiting histone deacetylase respectively. Negative autoregulation by HNF-4alpha1 was abrogated by overexpressed Sp1. Transcriptional suppression by HNF-4alpha1 independently of its transactivation function may extend the scope of its transcriptional activity to interference with docking of the pre-transcriptional initiation complex to TATA-less promoters.
Mesh Terms:
Cell Line, Gene Expression Regulation, Hepatocyte Nuclear Factor 4, Humans, Promoter Regions, Genetic, Transcriptional Activation
Cell Line, Gene Expression Regulation, Hepatocyte Nuclear Factor 4, Humans, Promoter Regions, Genetic, Transcriptional Activation
Biochem. J.
Date: May. 15, 2005
PubMed ID: 15651981
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