Identification of adjacent binding sites for the YY1 and E4BP4 transcription factors in the ovine PrP (Prion) gene promoter

Stewart T G Burgess, Cuicui Shen, Laura A Ferguson, Gerard T O'Neill, Kevin Docherty, Nora Hunter, Wilfred Goldmann

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The PrP gene encodes the cellular isoform of the prion protein (PrP(c)) which has been shown to be crucial to the development of transmissible spongiform encephalopathies (TSEs). PrP knock-out mice, which do not express endogenous PrP(c), exhibit resistance to TSE disease. The regulation of PrP gene expression represents, therefore, a crucial factor in the development of TSEs. Two sequence motifs in the PrP promoter (positions -287 to -263 from transcriptional start) were previously reported as being highly conserved, and it was suggested that they represent binding sites for as yet unidentified transcription factors. To test this hypothesis, binding of nuclear proteins was analyzed by electrophoretic mobility shift assays using ovine or murine cells and tissues with radiolabeled DNA probes containing the conserved motif sequences. Specific binding was observed to both motifs, and polymorphic variants of these motifs exhibited differential binding. Two proteins bound to these motifs were identified as the Yin Yang 1 (YY1) (motif 1) and E4BP4 (motif 2) transcription factors. Functional promoter analysis of four different promoter variants revealed that motif 1 (YY1) was associated with inhibitory activity in the context of the PrP promoter, whereas motif 2 (E4BP4) was linked to a slight enhancing activity. This represents the first demonstration of binding of nuclear factors to two highly conserved DNA sequence motifs within mammalian PrP promoters. The action of these factors on the PrP promoter is haplotype-specific, leading us to propose that the prion protein expression pattern and, with it, the distribution of TSE infectivity may be associated with PrP promoter genotype.
Original languageEnglish
Pages (from-to)6716-6724
Number of pages9
JournalThe Journal of Biological Chemistry
Volume284
Issue number11
DOIs
Publication statusPublished - 13 Mar 2009

Fingerprint

Yin-Yang
Prion Diseases
Prions
Sheep
Transcription Factors
Genes
Binding Sites
Electrophoretic mobility
Functional analysis
Conserved Sequence
DNA sequences
DNA Probes
Nuclear Proteins
Gene expression
Assays
Protein Isoforms
Demonstrations
Tissue
Nucleotide Motifs
Gene Expression Regulation

Keywords

  • Animals
  • Basic-Leucine Zipper Transcription Factors
  • Hela Cells
  • Humans
  • Mice
  • PrPC Proteins
  • Prion Diseases
  • Response Elements
  • Sheep
  • YY1 Transcription Factor

Cite this

Burgess, S. T. G., Shen, C., Ferguson, L. A., O'Neill, G. T., Docherty, K., Hunter, N., & Goldmann, W. (2009). Identification of adjacent binding sites for the YY1 and E4BP4 transcription factors in the ovine PrP (Prion) gene promoter. The Journal of Biological Chemistry, 284(11), 6716-6724. https://doi.org/10.1074/jbc.M807065200

Identification of adjacent binding sites for the YY1 and E4BP4 transcription factors in the ovine PrP (Prion) gene promoter. / Burgess, Stewart T G; Shen, Cuicui; Ferguson, Laura A; O'Neill, Gerard T; Docherty, Kevin; Hunter, Nora; Goldmann, Wilfred.

In: The Journal of Biological Chemistry, Vol. 284, No. 11, 13.03.2009, p. 6716-6724.

Research output: Contribution to journalArticle

Burgess, STG, Shen, C, Ferguson, LA, O'Neill, GT, Docherty, K, Hunter, N & Goldmann, W 2009, 'Identification of adjacent binding sites for the YY1 and E4BP4 transcription factors in the ovine PrP (Prion) gene promoter' The Journal of Biological Chemistry, vol. 284, no. 11, pp. 6716-6724. https://doi.org/10.1074/jbc.M807065200
Burgess, Stewart T G ; Shen, Cuicui ; Ferguson, Laura A ; O'Neill, Gerard T ; Docherty, Kevin ; Hunter, Nora ; Goldmann, Wilfred. / Identification of adjacent binding sites for the YY1 and E4BP4 transcription factors in the ovine PrP (Prion) gene promoter. In: The Journal of Biological Chemistry. 2009 ; Vol. 284, No. 11. pp. 6716-6724.
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AU - Shen, Cuicui

AU - Ferguson, Laura A

AU - O'Neill, Gerard T

AU - Docherty, Kevin

AU - Hunter, Nora

AU - Goldmann, Wilfred

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KW - Mice

KW - PrPC Proteins

KW - Prion Diseases

KW - Response Elements

KW - Sheep

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