Format

Send to

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

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

Author information

1
Laboratory of Neurodegenerative Disorders, Department of Neurology, Hospital Clínic of Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) University of Barcelona (UB), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain Cell Therapy Program, Faculty of Medicine, University of Barcelona (UB), Barcelona, Spain ruben.fernandez.santiago@gmail.com ezquerra@clinic.ub.es.
2
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain Neurodegenerative Diseases Research Laboratory, Hospital Vall d'Hebron Vall d'Hebron Research Institute (VHIR) Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
3
Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona (UB) Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
4
Institute for Biomedicine (IBUB) University of Barcelona (UB), Barcelona, Spain.
5
Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain Centre for Networked Biomedical Research on Bioengineering Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain.
6
Department of Statistics, University of Barcelona (UB), Barcelona, Spain Department of Statistics, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.
7
Department of Statistics, University of Barcelona (UB), Barcelona, Spain.
8
Departament d'Estructura i Constituents de la Matèria (ECM), Facultat de Física, University of Barcelona (UB), Barcelona, Spain.
9
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain Institute of Biomedicine of Seville (IBiS) Hospital Universitario Virgen del Rocío Consejo Superior de Investigaciones Científicas (CSIC) University of Seville, Seville, Spain.
10
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain Cell Therapy Program, Faculty of Medicine, University of Barcelona (UB), Barcelona, Spain Department of Cell Biology, Immunology and Neuroscience, Faculty of Medicine, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) University of Barcelona (UB), Barcelona, Spain.
11
Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain Centre for Networked Biomedical Research on Bioengineering Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
12
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain Neurodegenerative Diseases Research Laboratory, Hospital Vall d'Hebron Vall d'Hebron Research Institute (VHIR) Universitat Autònoma de Barcelona (UAB), Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
13
Institute for Biomedicine (IBUB) University of Barcelona (UB), Barcelona, Spain Department of Molecular and Translational Medicine, University of Brescia and National Institute of Neuroscience, Brescia, Italy.
14
Laboratory of Neurodegenerative Disorders, Department of Neurology, Hospital Clínic of Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) University of Barcelona (UB), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain Cell Therapy Program, Faculty of Medicine, University of Barcelona (UB), Barcelona, Spain Movement Disorders Unit, Department of Neurology, Hospital Clínic of Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) University of Barcelona (UB), Barcelona, Spain.

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

PMID:
26516212
PMCID:
PMC4693505
DOI:
10.15252/emmm.201505439
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center