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DNA methylation analysis in idiopathic and LRRK2-associated Parkinson's disease (PD)

ABSTRACT: We performed a genome-wide DNA methylation study in induced pluripotent stem cells (IPSC)-derived dopaminergic neurons (DAn) generated from keratinocytes of monogenic and sporadic Parkinson disease (PD) patients as well as of healthy subjects. We observed extensive DNA methylation changes in DAn from PD patients. These changes were neither present in the original keratinocytes nor in the undifferentiated IPSCs, suggesting latent molecular defects in PD keratinocytes that are manifested only upon differentiation into DAn. We also found that enhancers showing abnormal DNA hypermethylation in PD were enriched for binding sites of transcription factors such as FOXA1, NR3C1, HNF4A and FOSL2 which are involved in the survival of DAn and showed reduced expression. These data suggest that aberrant epigenomic remodeling of IPSC-derived DAn in PD is mediated by the down-regulation of key transcription factors. Our study suggests that future cell replacement strategies should pay careful attention to the correct epigenomic status of the reprogrammed cells, especially when using patient own skin cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51921 | GEO | 2015/12/01

SECONDARY ACCESSION(S): PRJNA225815

REPOSITORIES: GEO

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Project description:To determine IL-17-induced global transcriptome changes in midbrain neurons derived from induced pluripotent stem cells (iPSC) from three sporadic Parkinson's disease (PD) patients and three age- and sex-machted controls, deep RNA sequencing (RNA-Seq) of IL-17-treated and untreated PD and control iPSC-dderived midbrain neurons was performed. Total RNA was isolated from untreated and IL-17-treated cells with the TruSeq RNA Sample Preparation Kit v2 (Illumina). RNA libraries were quantified using the KAPA SYBR FAST ABI Prism Library Quantification Kit (Kapa Biosystems) and cluster generation was performed on the cBot with the TruSeq SR Cluster Kit v3 (Illumina). The sequencing run was performed on a HiSeq 1000 instrument (Illumina) using the indexed, 50 cycles single read (SR) protocol and the TruSeq SBS v3 Kit (Illumina). Image analysis and base calling resulted in .bcl files that were then converted into .fastQ files by the CASAVA1.8.2 software. FastQ files were aligned to the human genome (hg19) using STAR.and annotated with gencode.v19. DESeq2 was used to determine differential expression. Criteria to determine significantly dysregulated genes were as follows: adjusted p-value below 0.05 and log2FC (fold change) of greater than one. Only genes with a mean expression value of greater than one RPKM (reads per kilobase per million mapped reads) throughout the dataset were considered. Control and PD samples were analyzed as two independent datasets. Upon IL-17 treatment only 17 genes were found to be dysregulated in controls but 125 genes were dysregulated in iPSC-derived midbrain neurons from PD patients. The 125 IL-17-dependent genes in PD iPSC-derived neurons separated the treated from untreated PD samples using an unsupervised, hierarchical clustering applying an Euclidean distance metric. More detailed study information can be found in Sommer A, Maxreiter F, Krach F, Fadler T, Grosch J, Maroni M, Graef D, Eberhardt E, Riemenschneider MJ, Yeo GW, Kohl Z, Xiang W, Gage FH, Winkler J, Prots I, Winner B. Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease. Cell Stem Cell. 2018 Jul 5;23(1):123-131.e6. doi: 10.1016/j.stem.2018.06.015. PMID: 29979986

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DNA methylation analysis in idiopathic and LRRK2-associated Parkinson's disease (PD)

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