HNF-4α (hepatocyte nuclear factor-4α) is required for tissue-specific expression of many of the hepatic, pancreatic, enteric and renal traits. Heterozygous HNF-4α mutants are inflicted by MODY-1 (maturity onset diabetes of the young type-1). HNF-4α expression is reported here to be negatively autoregulated by HNF-4α1 and to be activated by dominant-negative HNF-4α1. Deletion and chromatin immunoprecipitation analysis indicated that negative autoregulation by HNF-4α1 was mediated by its association with the TATA-less HNF-4α core promoter enriched in Sp1, but lacking DR-1 response elements. Also, negative autoregulation by HNF-4α1 was independent of its transactivation function, being similarly exerted by transcriptional-defective MODY-1 missense mutants of HNF-4α1, or under conditions of suppressing or enhancing HNF-4α activity by small heterodimer partner or by inhibiting histone deacetylase respectively. Negative autoregulation by HNF-4α1 was abrogated by overexpressed Sp1. Transcriptional suppression by HNF-4α1 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.
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Research Article|
May 10 2005
Negative autoregulation of HNF-4α gene expression by HNF-4α1
Judith MAGENHEIM
;
Judith MAGENHEIM
1Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120, Israel
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Rachel HERTZ
;
Rachel HERTZ
1Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120, Israel
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Ina BERMAN
;
Ina BERMAN
1Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120, Israel
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Janna NOUSBECK
;
Janna NOUSBECK
1Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120, Israel
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Jacob BAR-TANA
Jacob BAR-TANA
1
1Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120, Israel
1To whom correspondence should be addressed (email bartanaj@cc.huji.ac.il).
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Biochem J (2005) 388 (1): 325–332.
Article history
Received:
October 27 2004
Revision Received:
January 10 2005
Accepted:
January 14 2005
Accepted Manuscript online:
January 14 2005
Citation
Judith MAGENHEIM, Rachel HERTZ, Ina BERMAN, Janna NOUSBECK, Jacob BAR-TANA; Negative autoregulation of HNF-4α gene expression by HNF-4α1. Biochem J 15 May 2005; 388 (1): 325–332. doi: https://doi.org/10.1042/BJ20041802
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