Histone deacetylase inhibition modulates histone acetylation at gene promoter regions and affects genome-wide gene transcription in Schistosoma mansoni

PLoS Negl Trop Dis. 2017 Apr 13;11(4):e0005539. doi: 10.1371/journal.pntd.0005539. eCollection 2017 Apr.

Abstract

Background: Schistosomiasis is a parasitic disease infecting hundreds of millions of people worldwide. Treatment depends on a single drug, praziquantel, which kills the Schistosoma spp. parasite only at the adult stage. HDAC inhibitors (HDACi) such as Trichostatin A (TSA) induce parasite mortality in vitro (schistosomula and adult worms), however the downstream effects of histone hyperacetylation on the parasite are not known.

Methodology/principal findings: TSA treatment of adult worms in vitro increased histone acetylation at H3K9ac and H3K14ac, which are transcription activation marks, not affecting the unrelated transcription repression mark H3K27me3. We investigated the effect of TSA HDACi on schistosomula gene expression at three different time points, finding a marked genome-wide change in the transcriptome profile. Gene transcription activity was correlated with changes on the chromatin acetylation mark at gene promoter regions. Moreover, combining expression data with ChIP-Seq public data for schistosomula, we found that differentially expressed genes having the H3K4me3 mark at their promoter region in general showed transcription activation upon HDACi treatment, compared with those without the mark, which showed transcription down-regulation. Affected genes are enriched for DNA replication processes, most of them being up-regulated. Twenty out of 22 genes encoding proteins involved in reducing reactive oxygen species accumulation were down-regulated. Dozens of genes encoding proteins with histone reader motifs were changed, including SmEED from the PRC2 complex. We targeted SmEZH2 methyltransferase PRC2 component with a new EZH2 inhibitor (GSK343) and showed a synergistic effect with TSA, significantly increasing schistosomula mortality.

Conclusions/significance: Genome-wide gene expression analyses have identified important pathways and cellular functions that were affected and may explain the schistosomicidal effect of TSA HDACi. The change in expression of dozens of histone reader genes involved in regulation of the epigenetic program in S. mansoni can be used as a starting point to look for possible novel schistosomicidal targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Chromatin / genetics
  • DNA Replication
  • Down-Regulation
  • Female
  • Genome, Helminth
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histones / genetics*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Indazoles / pharmacology*
  • Male
  • Molecular Docking Simulation
  • Promoter Regions, Genetic
  • Pyridones / pharmacology*
  • Schistosoma mansoni / drug effects*
  • Schistosoma mansoni / genetics*
  • Transcriptome
  • Up-Regulation

Substances

  • Chromatin
  • GSK343
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Indazoles
  • Pyridones
  • trichostatin A

Grant support

This work was supported by a grant from the European Union’s Seventh Framework Programme under grant agreement no. 602080. LA and ASAP were supported by fellowships from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). LFS was supported by a fellowship from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). SVA was also supported by institutional funds from Fundação Butantan and received an established investigator fellowship award from CNPq, Brasil. The work of RP was also supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS), the Institut Pasteur de Lille and the Université de Lille. The work of CR was also supported by institutional funds from the CNRS, the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université de Strasbourg, the French Infrastructure for Integrated Structural Biology (FRISBI; ANR-10-INSB-05-01), and by Instruct (ESFRI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.