Repression by Groucho/TLE/Grg proteins: genomic site recruitment generates compacted chromatin in vitro and impairs activator binding in vivo

Mol Cell. 2007 Oct 26;28(2):291-303. doi: 10.1016/j.molcel.2007.10.002.

Abstract

Groucho-related (Gro/TLE/Grg) corepressors meditate embryonic segmentation, dorsal-ventral patterning, neurogenesis, and Notch and Wnt signaling. Although Gro/TLE/Grgs disrupt activator complexes and recruit histone deacetylases (HDAC), activator complexes can be disrupted in various ways, HDAC recruitment does not account for full corepressor activity, and a direct role for Gro/TLE/Grg binding and altering chromatin structure has not been explored. Using diverse chromatin substrates in vitro, we show that Grg3 creates higher-order, condensed complexes of polynucleosome arrays. Surprisingly, such complexes are in an open, exposed configuration. We find that chromatin binding enables Grg3 recruitment by a transcription factor and the creation of a closed, poorly accessible domain spanning three to four nucleosomes. Targeted recruitment of Grg3 blankets a similar-sized region in vivo, impairing activator recruitment and repressing transcription. These activities of a Groucho protein represent a newly discovered mechanism which differs from that of other classes of corepressors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • CHO Cells
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Chromatin / chemistry
  • Chromatin / metabolism*
  • Chromatin Assembly and Disassembly*
  • Cricetinae
  • Cricetulus
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enhancer Elements, Genetic
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Homeodomain Proteins / metabolism
  • Humans
  • Mice
  • Nucleic Acid Conformation
  • Nucleosomes / metabolism
  • Promoter Regions, Genetic
  • Protein Conformation
  • Protein Structure, Tertiary
  • Recombinant Proteins / metabolism
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcription, Genetic*
  • Transcriptional Activation*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Chromatin
  • DNA-Binding Proteins
  • Hepatocyte Nuclear Factor 3-alpha
  • Homeodomain Proteins
  • Nucleosomes
  • Recombinant Proteins
  • Repressor Proteins
  • Hepatocyte Nuclear Factor 3-beta