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The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression.

Regulation of NF-kappaB transactivation function is controlled at several levels, including interactions with coactivator proteins. Here we show that the transactivation function of NF-kappaB is also regulated through interaction of the p65 (RelA) subunit with histone deacetylase (HDAC) corepressor proteins. Our results show that inhibition of HDAC activity with trichostatin A (TSA) results in an increase in both basal and induced expression of an integrated NF-kappaB-dependent reporter gene. Chromatin immunoprecipitation (ChIP) assays show that TSA treatment causes hyperacetylation of the wild-type integrated NF-kappaB-dependent reporter but not of a mutant version in which the NF-kappaB binding sites were mutated. Expression of HDAC1 and HDAC2 repressed tumor necrosis factor (TNF)-induced NF-kappaB-dependent gene expression. Consistent with this, we show that HDAC1 and HDAC2 target NF-kappaB through a direct association of HDAC1 with the Rel homology domain of p65. HDAC2 does not interact with NF-kappaB directly but can regulate NF-kappaB activity through its association with HDAC1. Finally, we show that inhibition of HDAC activity with TSA causes an increase in both basal and TNF-induced expression of the NF-kappaB-regulated interleukin-8 (IL-8) gene. Similar to the wild-type integrated NF-kappaB-dependent reporter, ChIP assays showed that TSA treatment resulted in hyperacetylation of the IL-8 promoter. These data indicate that the transactivation function of NF-kappaB is regulated in part through its association with HDAC corepressor proteins. Moreover, it suggests that the association of NF-kappaB with the HDAC1 and HDAC2 corepressor proteins functions to repress expression of NF-kappaB-regulated genes as well as to control the induced level of expression of these genes.

Pubmed ID: 11564889

Authors

  • Ashburner BP
  • Westerheide SD
  • Baldwin AS

Journal

Molecular and cellular biology

Publication Data

October 20, 2001

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI35098
  • Agency: NCI NIH HHS, Id: CA 73756

Mesh Terms

  • 3T3 Cells
  • Acetylation
  • Animals
  • Binding Sites
  • Blotting, Northern
  • Blotting, Western
  • COS Cells
  • Cell Line
  • Chromatin
  • Down-Regulation
  • Enzyme Inhibitors
  • Gene Expression Regulation, Enzymologic
  • HeLa Cells
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylases
  • Humans
  • Hydroxamic Acids
  • Luciferases
  • Mice
  • NF-kappa B
  • Plasmids
  • Precipitin Tests
  • Protein Binding
  • Repressor Proteins
  • Transcription Factor RelA
  • Transcriptional Activation
  • Transfection