Dopamine signaling leads to loss of Polycomb repression and aberrant gene activation in experimental parkinsonism

PLoS Genet. 2014 Sep 25;10(9):e1004574. doi: 10.1371/journal.pgen.1004574. eCollection 2014 Sep.

Abstract

Polycomb group (PcG) proteins bind to and repress genes in embryonic stem cells through lineage commitment to the terminal differentiated state. PcG repressed genes are commonly characterized by the presence of the epigenetic histone mark H3K27me3, catalyzed by the Polycomb repressive complex 2. Here, we present in vivo evidence for a previously unrecognized plasticity of PcG-repressed genes in terminally differentiated brain neurons of parkisonian mice. We show that acute administration of the dopamine precursor, L-DOPA, induces a remarkable increase in H3K27me3S28 phosphorylation. The induction of the H3K27me3S28p histone mark specifically occurs in medium spiny neurons expressing dopamine D1 receptors and is dependent on Msk1 kinase activity and DARPP-32-mediated inhibition of protein phosphatase-1. Chromatin immunoprecipitation (ChIP) experiments showed that increased H3K27me3S28p was accompanied by reduced PcG binding to regulatory regions of genes. An analysis of the genome wide distribution of L-DOPA-induced H3K27me3S28 phosphorylation by ChIP sequencing (ChIP-seq) in combination with expression analysis by RNA-sequencing (RNA-seq) showed that the induction of H3K27me3S28p correlated with increased expression of a subset of PcG repressed genes. We found that induction of H3K27me3S28p persisted during chronic L-DOPA administration to parkisonian mice and correlated with aberrant gene expression. We propose that dopaminergic transmission can activate PcG repressed genes in the adult brain and thereby contribute to long-term maladaptive responses including the motor complications, or dyskinesia, caused by prolonged administration of L-DOPA in Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
  • Female
  • Gene Expression Regulation* / drug effects
  • Genetic Loci
  • Histones / metabolism
  • Levodopa / pharmacology
  • Mice
  • Mice, Knockout
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / metabolism*
  • Phosphorylation / drug effects
  • Polycomb-Group Proteins / genetics*
  • Protein Binding
  • RNA, Messenger / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Signal Transduction*
  • Transcriptional Activation*

Substances

  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Histones
  • Polycomb-Group Proteins
  • RNA, Messenger
  • Levodopa
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • Dopamine

Associated data

  • GEO/GSE60703

Grant support

This work was supported by grants from the Swedish Research Council (13482 to GF), the Karolinska Institutet/National Institute of Health Graduate Partnership Program (to GF), the Parkinson Foundation in Sweden (to GF), the Lundbeck Foundation (to KH) and the Danish National Research Foundation (to KH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.