Negative autoregulation of HNF-4α gene expression by HNF-4α1

Judith Magenheim, Rachel Hertz, Ina Berman, Janna Nousbeck, Jacob Bar-Tana*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

HNF-4α (hepatocyte nuclear factor-4α) is required for tissuespecific 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-4α I and to be activated by dominant-negative HNF-4α 1. 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.

Original languageAmerican English
Pages (from-to)325-332
Number of pages8
JournalBiochemical Journal
Volume388
Issue number1
DOIs
StatePublished - 15 May 2005

Keywords

  • Hepatocyte nuclear factor-4α (HNF-4α)
  • Maturity onset diabetes of the young (MODY)
  • Sp1
  • Transcription

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