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DNA Methylation Alterations in Ipsc- and Hesc-Derived Neurons

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DNA Methylation Alterations in Ipsc- and Hesc-Derived Neurons de Boni et al. Clinical Epigenetics (2018) 10:13 DOI 10.1186/s13148-018-0440-0 RESEARCH Open Access DNA methylation alterations in iPSC- and hESC-derived neurons: potential implications for neurological disease modeling Laura de Boni1,2† , Gilles Gasparoni3†, Carolin Haubenreich2†, Sascha Tierling3, Ina Schmitt1,4, Michael Peitz2,4, Philipp Koch2, Jörn Walter3*, Ullrich Wüllner1,4* and Oliver Brüstle2* Abstract Background: Genetic predisposition and epigenetic alterations are both considered to contribute to sporadic neurodegenerative diseases (NDDs) such as Parkinson’s disease (PD). Since cell reprogramming and the generation of induced pluripotent stem cells (iPSCs) are themselves associated with major epigenetic remodeling, it remains unclear to what extent iPSC-derived neurons lend themselves to model epigenetic disease-associated changes. A key question to be addressed in this context is whether iPSC-derived neurons exhibit epigenetic signatures typically observed in neurons derived from non-reprogrammed human embryonic stem cells (hESCs). Results: Here, we compare mature neurons derived from hESC and isogenic human iPSC generated from hESC-derived neural stem cells. Genome-wide 450 K-based DNA methylation and HT12v4 gene array expression analyses were complemented by a deep analysis of selected genes known to be involved in NDD. Our studies show that DNA methylation and gene expression patterns of isogenic hESC- and iPSC-derived neurons are markedly preserved on a genome-wide and single gene level. Conclusions: Overall, iPSC-derived neurons exhibit similar DNA methylation patterns compared to isogenic hESC-derived neurons. Further studies will be required to explore whether the epigenetic patterns observed in iPSC-derived neurons correspond to those detectable in native brain neurons. Keywords: DNA methylation, Isogenic stem cells, iPS cell-derived neurons Background pathophysiology of this devastating disorder or the The origin and pathophysiology of sporadic neurode- individual susceptibility [1]. generative diseases (NDDs) such as idiopathic Previously, we have identifiedsignificantlyreducedDNA Parkinson’s disease (iPD) still remain enigmatic. In methylation levels of SNCA intron 1 in PD brains [2]. In this regard, epigenetic alterations of genes including SK-N-SH cells, DNA demethylation of the SNCA intron α-synuclein (SNCA) could contribute to the 1—using the DNA methyltransferase inhibitor 5- Azacytidine—was associated with an increase in SNCA mRNA and α-synuclein protein expression [2]. This is an important finding as elevated α-synuclein protein levels * Correspondence: [email protected]; [email protected]; are directly linked to the development of PD [3, 4]. To [email protected] †Equal contributors date, these findings could not be verified in follow-up 3Institute for Genetics/Epigenetics, FR8.3 Life Sciences, Saarland University, studies [5] and/or in native neurons derived from iPD pa- Saarbrücken, Germany tients compared to controls due to the inaccessibility of 1Department of Neurology, University Hospital of Bonn, Bonn, Germany 2Institute of Reconstructive Neurobiology, Life & Brain Center, University of living disease-affected cells. Bonn, Bonn, Germany Full list of author information is available at the end of the article © The Author(s). 2018 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. de Boni et al. Clinical Epigenetics (2018) 10:13 Page 2 of 13 In this context, in vitro differentiated neural cells from compared to hESC-derived neurons. As a first step, we patient-derived induced pluripotent stem cells (iPSCs) compared isogenic hESC- and iPSC-derived neurons, couldprovideatooltostudyhumanneurons.Human which allow the analysis of DNA methylation differences iPSCs have indeed already been employed to dissect the independently of individual genetic variations. To that mechanisms of several mostly inherited NDDs [6–9]. iPSC- end, we already differentiated thoroughly the character- based models of PD, mainly focusing on familial forms of ized and stable populations of hESC-derived stable neural the disease, displayed some interesting and relevant pheno- stem cells (NSCs) from the female hESC line I3 into 6- types [10]. Consequently, patient-specific iPSC-derived neu- week-old neurons (Fig. 1). These hESC-derived NSCs, also rons could be used to establish in vitro models for iPD referred to as long-term self-renewing neuroepithelial allowing epigenetic and gene expression studies. Recently, a stem cells (lt-NES cells) differentiate predominantly into comprehensive study comprising epigenetic analyses in PD GABAergic neurons with a posterior identity correspond- iPSC models revealed an aberrant epigenome in iPSC- ing to the ventral hindbrain area [14]. We reprogrammed derived dopaminergic neurons (DAn) of iPD and LRRK2 these NSCs to iPSC and subsequently differentiated them PD patients [11]. These data suggest that cell-specific and into three clonal populations of iPSC-derived neurons, presumptive disease-associated epigenetic changes can be which were compared with neurons generated from the retrieved from iPSC-derived patient-specific neurons. Never- parental hESC (Fig. 1). A genome-wide analysis was car- theless, the process of induced reprogramming is based on ried out using Illumina 450 K bead arrays measuring erasing the existing epigenetic state of the cell of origin [12, DNA methylation levels at > 450.000 CpG sites covering 13]. One key question emerging in the context of pluripo- promoters and putative regulatory domains of all designa- tent stem cell-based disease modeling is whether iPSC- ble RefSeq genes. derived neurons display epigenetic patterns resembling A Pearson correlation analysis of gene-linked CpG those of neurons derived from non-reprogrammed human methylation revealed at least a 96% concordance of iPS- embryonic stem cells (hESCs). To address this question, we NSC and iPS-Neurons compared to their hESC-derived employed an isogenic stem cell system to compare DNA counterparts (Fig. 2a). The interclonal variance was methylation patterns of hESC- and iPSC-derived mature small; NSC and neurons derived from the three different neurons both generated from the same parental hESC line. iPSC clones showed a concordance for DNA methyla- Such an isogenic approach should eliminate differences due tion levels of at least 97% (Fig. 2a). to individual genetic variation. Specifically, we assessed (i) Differentially methylated CpGs (DMCGs) in iPSC- genome-wide DNA methylation of > 485.000 CpGs in po- derived neurons compared to their hESC-derived coun- tential regulatory elements such as promoters or enhancers, terparts (defined by a methylation difference > 20%) (ii) gene expression of > 47.000 transcripts, and (iii) DNA were analyzed in more detail; 8.680 (42.35%) of these methylation and gene expression changes of several NDD- DMCGs were hypomethylated, and 11.816 (57.65%) were related genes, in particular, SNCA. hypermethylated in iPS- compared to hES-Neurons (Fig. 2b). Transcription start sites were not overrepre- Results sented in these DMCGs compared to the overall 450 K Genome-wide and single gene DNA methylation patterns array annotation (Fig. 2c upper panels). More hypo- of isogenic hESC- and iPSC-derived neurons are very methylated CpGs were found in CpG islands (CGI) and similar more hypermethylated CpGs in non-CGI DNA se- The current study addressed the question whether iPSC- quences (Fig. 2c lower panels). We also analyzed the derived neurons display similar DNA methylation patterns standard deviation (> 0.2) of single DMCG in iPS-NSC Fig. 1 Isogenic human stem cell system. Stable populations of human embryonic stem cell (hESC)-derived neural stem cells (hES-NSC, female hESC line I3) were reprogrammed to pluripotency, and three iPSC clones were subsequently re-differentiated into neural stem cells (NSCs) and neurons de Boni et al. Clinical Epigenetics (2018) 10:13 Page 3 of 13 Fig. 2 Genome-wide DNA methylation analysis. a Pairwise correlation plots (Pearson correlation, genome-wide DNA methylation analysis) of hESC- and iPSC-derived NSC and neurons display high correlation coefficients (black: hES-NSC vs. iPS-NSC, blue: hES-Neurons vs. iPS-Neurons) and minimal interclonal variance (orange: comparison of iPS-NSC clone 1, clone 2, and clone 3; red: comparison of iPS-Neurons clone 1, clone 2, and clone 3). b Number of differentially hypo- and hypermethylated CpGs (DMCG) in iPS-Neurons compared to hES-Neurons. iPSC-derived neurons demonstrate slightly more hyper- than hypomethylated DMCG compared to hESC-derived neurons. c Annotation of hypo- and hypermethylated DMCG in terms of gene regulatory regions (intergenic gene regions, 1st exon, 3′ and 5′ untranslated region (UTR), gene body, promoter areas: transcription start sites (TSS) 1500 and 200; upper pie charts), and CpG islands (CpG islands and flanking regions before (N_Shelf, N_Shore) and after (S_Shelf, S_Shore) CpG islands; lower pie charts) in comparison to the overall distribution
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