Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation

EMBO J. 2011 Jan 19;30(2):249-62. doi: 10.1038/emboj.2010.318. Epub 2010 Dec 3.

Abstract

Histone acetyltransferases (HATs) GCN5 and PCAF (GCN5/PCAF) and CBP and p300 (CBP/p300) are transcription co-activators. However, how these two distinct families of HATs regulate gene activation remains unclear. Here, we show deletion of GCN5/PCAF in cells specifically and dramatically reduces acetylation on histone H3K9 (H3K9ac) while deletion of CBP/p300 specifically and dramatically reduces acetylations on H3K18 and H3K27 (H3K18/27ac). A ligand for nuclear receptor (NR) PPARδ induces sequential enrichment of H3K18/27ac, RNA polymerase II (Pol II) and H3K9ac on PPARδ target gene Angptl4 promoter, which correlates with a robust Angptl4 expression. Inhibiting transcription elongation blocks ligand-induced H3K9ac, but not H3K18/27ac, on the Angptl4 promoter. Finally, we show GCN5/PCAF and GCN5/PCAF-mediated H3K9ac correlate with, but are surprisingly dispensable for, NR target gene activation. In contrast, CBP/p300 and their HAT activities are essential for ligand-induced Pol II recruitment on, and activation of, NR target genes. These results highlight the substrate and site specificities of HATs in cells, demonstrate the distinct roles of GCN5/PCAF- and CBP/p300-mediated histone acetylations in gene activation, and suggest an important role of CBP/p300-mediated H3K18/27ac in NR-dependent transcription.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Angiopoietin-like 4 Protein
  • Angiopoietins / genetics
  • Animals
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism*
  • Gene Knockout Techniques
  • Histones / metabolism*
  • Humans
  • Mass Spectrometry
  • Mice
  • PPAR delta / agonists
  • PPAR delta / metabolism*
  • Promoter Regions, Genetic / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Substrate Specificity
  • Thiazoles / metabolism
  • Thiazoles / pharmacology
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / physiology*
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism*

Substances

  • ANGPTL4 protein, human
  • Angiopoietin-like 4 Protein
  • Angiopoietins
  • GW 501516
  • Histones
  • PPAR delta
  • Thiazoles
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor