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

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 monogen...

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Detalles Bibliográficos
Autores: Fernández Santiago, Rubén, Carballo Carbajal, Iria, Castellano, Giancarlo, Torrent Juan, Roger, Richaud-Patin, Yvonne, Sánchez Danés, Adriana, Vilarrasa Blasi, Roser, Sànchez, Àlex (Sànchez Pla), Mosquera Mayo, José Luis, Soriano i Fradera, Jordi, López Barneo, José, Canals i Coll, Josep M., Alberch i Vié, Jordi, 1959-, Raya Chamorro, Ángel, Vila Farré, Miquel, Consiglio, Antonella, Martín-Subero, José Ignacio, Ezquerra Trabalón, Mario, Tolosa, Eduardo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/188109
Acceso en línea:https://hdl.handle.net/2445/188109
Access Level:acceso abierto
Palabra clave:Malaltia de Parkinson
ADN
Parkinson's disease
DNA
Descripción
Sumario: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.

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