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 wit...
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-10-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201505439 |
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| author | Rubén Fernández‐Santiago Iria Carballo‐Carbajal Giancarlo Castellano Roger Torrent Yvonne Richaud Adriana Sánchez‐Danés Roser Vilarrasa‐Blasi Alex Sánchez‐Pla José Luis Mosquera Jordi Soriano José López‐Barneo Josep M Canals Jordi Alberch Ángel Raya Miquel Vila Antonella Consiglio José I Martín‐Subero Mario Ezquerra Eduardo Tolosa |
| author_facet | Rubén Fernández‐Santiago Iria Carballo‐Carbajal Giancarlo Castellano Roger Torrent Yvonne Richaud Adriana Sánchez‐Danés Roser Vilarrasa‐Blasi Alex Sánchez‐Pla José Luis Mosquera Jordi Soriano José López‐Barneo Josep M Canals Jordi Alberch Ángel Raya Miquel Vila Antonella Consiglio José I Martín‐Subero Mario Ezquerra Eduardo Tolosa |
| author_sort | Rubén Fernández‐Santiago |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-007509ba6a4d4d19940a0fff72f98b85 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-10-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-007509ba6a4d4d19940a0fff72f98b852025-08-20T03:43:21ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-10-017121529154610.15252/emmm.201505439Aberrant epigenome in iPSC‐derived dopaminergic neurons from Parkinson's disease patientsRubén Fernández‐Santiago0Iria Carballo‐Carbajal1Giancarlo Castellano2Roger Torrent3Yvonne Richaud4Adriana Sánchez‐Danés5Roser Vilarrasa‐Blasi6Alex Sánchez‐Pla7José Luis Mosquera8Jordi Soriano9José López‐Barneo10Josep M Canals11Jordi Alberch12Ángel Raya13Miquel Vila14Antonella Consiglio15José I Martín‐Subero16Mario Ezquerra17Eduardo Tolosa18Laboratory of Neurodegenerative Disorders, Department of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB)Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona (UB), Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Institute for Biomedicine (IBUB), University of Barcelona (UB)Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC)Institute for Biomedicine (IBUB), University of Barcelona (UB)Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona (UB), Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Department of Statistics, University of Barcelona (UB)Department of Statistics, University of Barcelona (UB)Departament d'Estructura i Constituents de la Matèria (ECM), Facultat de Física, University of Barcelona (UB)Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC)Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)Institute for Biomedicine (IBUB), University of Barcelona (UB)Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona (UB), Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Laboratory of Neurodegenerative Disorders, Department of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB)Laboratory of Neurodegenerative Disorders, Department of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB)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.https://doi.org/10.15252/emmm.201505439DNA methylationdopaminergic neuroninduced pluripotent stem cellParkinson's diseasetranscription factor |
| spellingShingle | Rubén Fernández‐Santiago Iria Carballo‐Carbajal Giancarlo Castellano Roger Torrent Yvonne Richaud Adriana Sánchez‐Danés Roser Vilarrasa‐Blasi Alex Sánchez‐Pla José Luis Mosquera Jordi Soriano José López‐Barneo Josep M Canals Jordi Alberch Ángel Raya Miquel Vila Antonella Consiglio José I Martín‐Subero Mario Ezquerra Eduardo Tolosa Aberrant epigenome in iPSC‐derived dopaminergic neurons from Parkinson's disease patients EMBO Molecular Medicine DNA methylation dopaminergic neuron induced pluripotent stem cell Parkinson's disease transcription factor |
| title | Aberrant epigenome in iPSC‐derived dopaminergic neurons from Parkinson's disease patients |
| title_full | Aberrant epigenome in iPSC‐derived dopaminergic neurons from Parkinson's disease patients |
| title_fullStr | Aberrant epigenome in iPSC‐derived dopaminergic neurons from Parkinson's disease patients |
| title_full_unstemmed | Aberrant epigenome in iPSC‐derived dopaminergic neurons from Parkinson's disease patients |
| title_short | Aberrant epigenome in iPSC‐derived dopaminergic neurons from Parkinson's disease patients |
| title_sort | aberrant epigenome in ipsc derived dopaminergic neurons from parkinson s disease patients |
| topic | DNA methylation dopaminergic neuron induced pluripotent stem cell Parkinson's disease transcription factor |
| url | https://doi.org/10.15252/emmm.201505439 |
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