Dynamic acetylation of all lysine-4 trimethylated histone H3 is evolutionarily conserved and mediated by p300/CBP

Proc Natl Acad Sci U S A. 2011 May 10;108(19):7814-9. doi: 10.1073/pnas.1100099108. Epub 2011 Apr 25.

Abstract

Histone modifications are reported to show different behaviors, associations, and functions in different genomic niches and organisms. We show here that rapid, continuous turnover of acetylation specifically targeted to all K4-trimethylated H3 tails (H3K4me3), but not to bulk histone H3 or H3 carrying other methylated lysines, is a common uniform characteristic of chromatin biology in higher eukaryotes, being precisely conserved in human, mouse, and Drosophila. Furthermore, dynamic acetylation targeted to H3K4me3 is mediated by the same lysine acetyltransferase, p300/cAMP response element binding (CREB)-binding protein (CBP), in both mouse and fly cells. RNA interference or chemical inhibition of p300/CBP using a newly discovered small molecule inhibitor, C646, blocks dynamic acetylation of H3K4me3 globally in mouse and fly cells, and locally across the promoter and start-site of inducible genes in the mouse, thereby disrupting RNA polymerase II association and the activation of these genes. Thus, rapid dynamic acetylation of all H3K4me3 mediated by p300/CBP is a general, evolutionarily conserved phenomenon playing an essential role in the induction of immediate-early (IE) genes. These studies indicate a more global function of p300/CBP in mediating rapid turnover of acetylation of all H3K4me3 across the nuclei of higher eukaryotes, rather than a tight promoter-restricted function targeted by complex formation with specific transcription factors.

Publication types

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

MeSH terms

  • Acetylation
  • Animals
  • Binding Sites
  • Cell Line
  • Drosophila / genetics
  • Drosophila / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Evolution, Molecular
  • Gene Knockdown Techniques
  • Genes, Immediate-Early
  • Genes, fos
  • Genes, jun
  • Histone Acetyltransferases / antagonists & inhibitors
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism
  • Histone Deacetylase Inhibitors / pharmacology
  • Histones / chemistry*
  • Histones / metabolism*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Lysine / chemistry
  • Mice
  • Promoter Regions, Genetic
  • Species Specificity
  • p300-CBP Transcription Factors / antagonists & inhibitors
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism*

Substances

  • Drosophila Proteins
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • trichostatin A
  • Histone Acetyltransferases
  • p300-CBP Transcription Factors
  • Lysine