Intracellular crotonyl-CoA Stimulates Transcription Through p300-catalyzed Histone Crotonylation

Mol Cell. 2015 Apr 16;58(2):203-15. doi: 10.1016/j.molcel.2015.02.029. Epub 2015 Mar 26.

Abstract

Acetylation of histones at DNA regulatory elements plays a critical role in transcriptional activation. Histones are also modified by other acyl moieties, including crotonyl, yet the mechanisms that govern acetylation versus crotonylation and the functional consequences of this "choice" remain unclear. We show that the coactivator p300 has both crotonyltransferase and acetyltransferase activities, and that p300-catalyzed histone crotonylation directly stimulates transcription to a greater degree than histone acetylation. Levels of histone crotonylation are regulated by the cellular concentration of crotonyl-CoA, which can be altered through genetic and environmental perturbations. In a cell-based model of transcriptional activation, increasing or decreasing the cellular concentration of crotonyl-CoA leads to enhanced or diminished gene expression, respectively, which correlates with the levels of histone crotonylation flanking the regulatory elements of activated genes. Our findings support a general principle wherein differential histone acylation (i.e., acetylation versus crotonylation) couples cellular metabolism to the regulation of gene expression.

Publication types

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

MeSH terms

  • Acetate-CoA Ligase / genetics
  • Acetate-CoA Ligase / metabolism
  • Acetylation
  • Acyl Coenzyme A / genetics
  • Acyl Coenzyme A / metabolism*
  • Cell Line
  • Cell-Free System
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Histones / metabolism*
  • Humans
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Molecular Sequence Data
  • RNA, Messenger / metabolism*
  • Transcriptional Activation*

Substances

  • Acyl Coenzyme A
  • Histones
  • Lipopolysaccharides
  • RNA, Messenger
  • crotonyl-coenzyme A
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • ACSS2 protein, human
  • Acetate-CoA Ligase

Associated data

  • GEO/GSE63889