Yin yang 1 protein negatively regulates high-density lipoprotein receptor gene transcription by disrupting binding of sterol regulatory element binding protein to the sterol regulatory element

Endocrinology. 2001 Jan;142(1):49-58. doi: 10.1210/endo.142.1.7868.

Abstract

Because the high-density lipoprotein receptor (HDL-R) is a key element in cholesterol homeostasis and a potential therapeutic target for hypercholesterolemic drugs, an understanding of HDL-R regulation is essential. The sterol regulatory element (SRE) binding protein-1a (SREBP-1a) was shown to positively regulate HDL-R gene expression through two SREs. SREBP-1a requires the presence of a coactivator like simian-virus-40-protein-1 (Sp1) to promote maximum activation of the HDL-R promoter. Negative regulatory factors are also known to play a role in cholesterol homeostasis, and the ubiquitous Yin Yang-1 zinc finger transcription factor (YY1) has been shown to repress several sterol-responsive gene promoters. A search of the rat HDL-R promoter revealed two putative YY1 binding sites (distal, -1329 to -1321; proximal, -1211 to -1203). Upon removal of both YY1 binding sites, YY1 was unable to repress HDL-R activation under basal (unstimulated) promoter conditions. However, YY1 was still an efficient transcriptional repressor for SREBP-1a-induced activation. YY1 was able to attenuate the transcriptional synergy caused by the combined actions of SREBP-1a and Sp1. Two-hybrid studies confirmed that YY1 bound with high affinity to SREBP-1a, and mobility shift assays demonstrated that YY1 could disrupt SREBP-1a binding to both SREs. The molecular consequence of YY1 intervention seems to override any positive interactions between Sp-1 and SREBP-1a and results in the disruption of SREBP-1a binding to the SREs in the HDL-R promoter.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • CCAAT-Enhancer-Binding Proteins / antagonists & inhibitors
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Carrier Proteins*
  • Cell Line
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Erythroid-Specific DNA-Binding Factors
  • Gene Expression Regulation / physiology*
  • Genes, Reporter
  • Glutathione Transferase / genetics
  • Humans
  • Lipoproteins, HDL*
  • Luciferases / genetics
  • Mice
  • Promoter Regions, Genetic
  • RNA-Binding Proteins*
  • Receptors, Lipoprotein / genetics*
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Proteins / metabolism
  • Regulatory Sequences, Nucleic Acid
  • Repressor Proteins / metabolism
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors / metabolism*
  • Transcription, Genetic / physiology*
  • Transfection
  • YY1 Transcription Factor

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Carrier Proteins
  • DNA-Binding Proteins
  • Erythroid-Specific DNA-Binding Factors
  • Lipoproteins, HDL
  • RNA-Binding Proteins
  • Receptors, Lipoprotein
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Repressor Proteins
  • SREBF1 protein, human
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • YY1 Transcription Factor
  • YY1 protein, human
  • Yy1 protein, mouse
  • high density lipoprotein receptors
  • high density lipoprotein binding protein
  • Luciferases
  • Glutathione Transferase