Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson's disease patients

EMBO Mol Med. 2015 Dec;7(12):1529-46. doi: 10.15252/emmm.201505439.

Abstract

The epigenomic landscape of Parkinson's disease (PD) remains unknown. We performed a genomewide DNA methylation and a transcriptome studies in induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) generated by cell reprogramming of somatic skin cells from patients with monogenic LRRK2-associated PD (L2PD) or sporadic PD (sPD), and healthy subjects. We observed extensive DNA methylation changes in PD DAn, and of RNA expression, which were common in L2PD and sPD. No significant methylation differences were present in parental skin cells, undifferentiated iPSCs nor iPSC-derived neural cultures not-enriched-in-DAn. These findings suggest the presence of molecular defects in PD somatic cells which manifest only upon differentiation into the DAn cells targeted in PD. The methylation profile from PD DAn, but not from controls, resembled that of neural cultures not-enriched-in-DAn indicating a failure to fully acquire the epigenetic identity own to healthy DAn in PD. The PD-associated hypermethylation was prominent in gene regulatory regions such as enhancers and was related to the RNA and/or protein downregulation of a network of transcription factors relevant to PD (FOXA1, NR3C1, HNF4A, and FOSL2). Using a patient-specific iPSC-based DAn model, our study provides the first evidence that epigenetic deregulation is associated with monogenic and sporadic PD.

Keywords: DNA methylation; Parkinson's disease; dopaminergic neuron; induced pluripotent stem cell; transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cellular Reprogramming
  • DNA Methylation
  • Dopaminergic Neurons / physiology*
  • Epigenomics
  • Gene Expression Profiling
  • Humans
  • Induced Pluripotent Stem Cells / physiology*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism

Substances

  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases