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.
Magenheim
Judith
J
Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120, Israel.
Hertz
Rachel
R
Berman
Ina
I
Nousbeck
Janna
J
Bar-Tana
Jacob
J
D002460:Cell Line; D005786:Gene Expression Regulation; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4