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

Fernández-Santiago, Ruben; Merkel, Angelika; Castellano, Giancarlo; Heath, Simon; Raya Chamorro, Ángel; Tolosa, Eduard; Martí, Maria José; Consiglio, Antonella; Ezquerra, Mario

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

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