Epigenetic control of microsomal prostaglandin E synthase-1 by HDAC-mediated recruitment of p300

J Lipid Res. 2017 Feb;58(2):386-392. doi: 10.1194/jlr.M072280. Epub 2016 Dec 2.

Abstract

Nonsteroidal anti-inflammatory drugs are the most widely used medicine to treat pain and inflammation, and to inhibit platelet function. Understanding the expression regulation of enzymes of the prostanoid pathway is of great medical relevance. Histone acetylation crucially controls gene expression. We set out to identify the impact of histone deacetylases (HDACs) on the generation of prostanoids and examine the consequences on vascular function. HDAC inhibition (HDACi) with the pan-HDAC inhibitor, vorinostat, attenuated prostaglandin (PG)E2 generation in the murine vasculature and in human vascular smooth muscle cells. In line with this, the expression of the key enzyme for PGE2 synthesis, microsomal PGE synthase-1 (PTGES1), was reduced by HDACi. Accordingly, the relaxation to arachidonic acid was decreased after ex vivo incubation of murine vessels with HDACi. To identify the underlying mechanism, chromatin immunoprecipitation (ChIP) and ChIP-sequencing analysis were performed. These results suggest that HDACs are involved in the recruitment of the transcriptional activator p300 to the PTGES1 gene and that HDACi prevented this effect. In line with the acetyltransferase activity of p300, H3K27 acetylation was reduced after HDACi and resulted in the formation of heterochromatin in the PTGES1 gene. In conclusion, HDAC activity maintains PTGES1 expression by recruiting p300 to its gene.

Keywords: epigenetics; histone deacetylase; prostaglandin E2; prostaglandins; smooth muscle cells; vascular biology.

MeSH terms

  • Acetylation
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Dinoprostone / biosynthesis
  • Dinoprostone / genetics
  • E1A-Associated p300 Protein / genetics*
  • E1A-Associated p300 Protein / metabolism
  • Gene Expression Regulation / drug effects
  • Histone Deacetylase 1 / antagonists & inhibitors
  • Histone Deacetylase 1 / genetics*
  • Histone Deacetylase Inhibitors / administration & dosage
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / administration & dosage
  • Mice
  • Prostaglandin-E Synthases / biosynthesis
  • Prostaglandin-E Synthases / genetics*
  • Protein Processing, Post-Translational / genetics
  • Transcription, Genetic / drug effects*
  • Vorinostat

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Vorinostat
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse
  • Hdac1 protein, mouse
  • Histone Deacetylase 1
  • Prostaglandin-E Synthases
  • Dinoprostone