Whole-genome DNA hyper-methylation in iPSC-derived dopaminergic neurons from Parkinson's disease patients

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• dc.contributor.author Fernández-Santiago, Ruben
• dc.contributor.author Merkel, Angelika
• dc.contributor.author Castellano, Giancarlo
• dc.contributor.author Heath, Simon
• dc.contributor.author Raya Chamorro, Ángel
• dc.contributor.author Tolosa, Eduard
• dc.contributor.author Martí, Maria José
• dc.contributor.author Consiglio, Antonella
• dc.contributor.author Ezquerra, Mario
• dc.date.accessioned 2019-09-27T08:15:55Z
• dc.date.available 2019-09-27T08:15:55Z
• dc.date.issued 2019
• dc.description.abstract Background: Parkinson’s disease (PD) is characterized by the loss of midbrain dopaminergic neurons (DAn). Previously, we described the presence of DNA hyper- and hypo-methylation alterations in induced pluripotent stem cells (iPSC)-derived DAn from PD patients using the Illumina 450K array which prominently covers gene regulatory regions. Methods: To expand and contextualize previous findings, we performed the first whole-genome DNA bisulfite sequencing (WGBS) using iPSC-derived DAn from representative PD subjects: one sporadic PD (sPD) patient, one monogenic LRRK2-associated PD patient (L2PD), and one control. Results: At the whole-genome level, we detected global DNA hyper-methylation in the PD which was similarly spread across the genome in both sPD and L2PD and mostly affected intergenic regions. Conclusion: This study implements previous epigenetic knowledge in PD at a whole genome level providing the first comprehensive and unbiased CpG DNA methylation data using iPSC-derived DAn from PD patients. Our results indicate that DAn from monogenic or sporadic PD exhibit global DNA hyper-methylation changes. Findings from this exploratory study are to be validated in further studies analyzing other PD cell models and patient tissues.
• dc.description.sponsorship This work was supported by the Fondo de Investigaciones Sanitarias of the Instituto de Salud Carlos III (ISCIII) to M.E. (grant # PI14/00426), the Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) to the Movement Disorders Unit of the Neurology Service from the Hospital Clínic de Barcelona to E.T., M.-J.M., R.F.-S., and M.E. (grant # PRI-16-2017). R.F.S. was supported by a Jóvenes Investigadores grant (#SAF2015-73508-JIN) through the Programa Estatal de Investigación, Desarrollo e Innovación Orientada a los Retos de la Sociedad (Plan Estatal de I+D+I 2013–2016) of the Spanish Ministry of Economy and Competitiveness (MINECO), and the Agencia Estatal de Investigación (AEI), which is cofunded by FEDER (AEI/FEDER/UE). Other funding included the grants BFU2013-49157-P, BFU2016-80870-P, and the European Research Council (ERC) 2012-StG (311736- PD-HUMMODEL) to A.C; ISCIII/FEDER (RD16/0011/0024) and Generalitat de Catalunya (iPS4BioMed SGR 2017–2019) to A.R.; and ISCIII/FEDER (PIE14/00061) to A.R.
• dc.format.mimetype application/pdf
• dc.identifier.citation Fernández-Santiago R, Merkel A, Castellano G, Heath S, Raya Á, Tolosa E, Martí MJ, Consiglio A, Ezquerra M. Whole-genome DNA hyper-methylation in iPSC-derived dopaminergic neurons from Parkinson's disease patients. Clin Epigenetics. 2019; 11(1):108. DOI 10.1186/s13148-019-0701-6
• dc.identifier.doi http://dx.doi.org/10.1186/s13148-019-0701-6
• dc.identifier.issn 1868-7075
• dc.identifier.uri http://hdl.handle.net/10230/42348
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Clinical Epigenetics. 2019; 11(1):108
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/311736
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2013-49157-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-80870-P
• dc.rights © The Author(s). 2019. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Parkinson disease (PD)
• dc.subject.keyword iPSC-derived DAn
• dc.subject.keyword DNA methylation
• dc.subject.keyword Whole-genome bisulfite sequencing (WGBS)
• dc.subject.keyword DMCpGs
• dc.subject.keyword Differentially methylated CpGs
• dc.title Whole-genome DNA hyper-methylation in iPSC-derived dopaminergic neurons from Parkinson's disease patients
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion