title: Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson's disease patients.
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.
authors.affiliation: 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.
authors.forename: Rubén
authors.initials: R
authors.lastname: Fernández-Santiago
authors.affiliation: 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.
authors.forename: Iria
authors.initials: I
authors.lastname: Carballo-Carbajal
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona (UB) Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castellano
authors.affiliation: Institute for Biomedicine (IBUB) University of Barcelona (UB), Barcelona, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Torrent
authors.affiliation: 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.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Richaud
authors.affiliation: Institute for Biomedicine (IBUB) University of Barcelona (UB), Barcelona, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: Sánchez-Danés
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona (UB) Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Vilarrasa-Blasi
authors.affiliation: Department of Statistics, University of Barcelona (UB), Barcelona, Spain Department of Statistics, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Sánchez-Pla
authors.affiliation: Department of Statistics, University of Barcelona (UB), Barcelona, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Mosquera
authors.affiliation: Departament d'Estructura i Constituents de la Matèria (ECM), Facultat de Física, University of Barcelona (UB), Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Soriano
authors.affiliation: 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.
authors.forename: José
authors.initials: J
authors.lastname: López-Barneo
authors.affiliation: 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.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Canals
authors.affiliation: 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.
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.affiliation: 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.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Raya
authors.affiliation: 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.
authors.forename: Miquel
authors.initials: M
authors.lastname: Vila
authors.affiliation: 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.
authors.forename: Antonella
authors.initials: A
authors.lastname: Consiglio
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona (UB) Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.affiliation: 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.
authors.forename: Mario
authors.initials: M
authors.lastname: Ezquerra
authors.affiliation: 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.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tolosa
mesh_terms: D065150:Cellular Reprogramming; D019175:DNA Methylation; D059290:Dopaminergic Neurons / Q000502:physiology*; D057890:Epigenomics; D020869:Gene Expression Profiling; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: DNA methylation; Parkinson's disease; dopaminergic neuron; induced pluripotent stem cell; transcription factor