Association of histone deacetylase with COUP-TF in tumorigenic Ad12-transformed cells and its potential role in shut-off of MHC class I transcription

Virology. 2000 Mar 15;268(2):319-28. doi: 10.1006/viro.1999.0181.

Abstract

Chicken ovalbumin upstream promoter-transcription factor (COUP-TF) is an orphan nuclear receptor that represses transcription of many genes. In adenovirus type 12 (Ad12) transformed cells, a high level of binding activity of COUP-TF to the major histocompatibility complex (MHC) class I enhancer correlates with the down-regulation of class I transcription, which, in turn, contributes to tumorigenesis. The mechanism by which COUP-TF represses transcription has yet to be elucidated. Here we show that COUP-TF represses transcription through its association with histone deacetylase. This was demonstrated using reciprocal binding assays that determined that the interaction between COUP-TF and histone deacetylase requires the COUP-TF C-terminal repression domain. Moreover, a histone deacetylase enzymatic activity was found to be associated with COUP-TF in Ad12-transformed cells. Transfection experiments further revealed that exogenous histone deacetylase facilitates transcriptional repression by COUP-TF. Also, supershift assays suggest that the transcriptional corepressor N-CoR, which is known to associate with histone deacetylases, is a part of the COUP-TF complex bound to the MHC class I enhancer R2 site. Finally, we provide evidence that inhibition of histone deacetylases relieves the repression of MHC class I expression in Ad12-transformed cells. Taken together these results support the notion that deacetylation of histones, mediated through COUP-TF, serves to down-regulate MHC class I transcription in Ad12-transformed cells.

Publication types

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

MeSH terms

  • Adenoviruses, Human / genetics*
  • Animals
  • Binding Sites
  • COUP Transcription Factor I
  • Cell Line, Transformed
  • Cell Transformation, Viral / genetics*
  • DNA-Binding Proteins / metabolism*
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Viral
  • Genes, MHC Class I / genetics*
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases / metabolism*
  • Histone Deacetylases / physiology*
  • L Cells
  • Mice
  • Peptide Fragments / physiology
  • Transcription Factors / metabolism*
  • Transcription, Genetic / genetics*
  • Transcription, Genetic / physiology*

Substances

  • COUP Transcription Factor I
  • DNA-Binding Proteins
  • Histone Deacetylase Inhibitors
  • Nr2f1 protein, mouse
  • Peptide Fragments
  • Transcription Factors
  • Histone Deacetylases