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RNA seq in IPSCs derived dopaminergic neurons comparison of SNORD116MD versus control

ABSTRACT: Introduction: A microdeletion including the SNORD116 gene (SNORD116 MD) has been shown to drive the Prader-Willi syndrome (PWS) phenotype. PWS is a neurodevelopmental disorder resulting from hypothalamic dysfunction implicating oxytocin (OXT) circuits. It is clinically characterized by early severe obesity, endocrine impairment, intellectual disability and psychiatric symptoms such as a lack of emotional regulation, impulsivity, and intense temper tantrums with outbursts. In addition, this syndrome is associated with a nutritional trajectory characterized by addiction-like behavior around food in adulthood. PWS is related to the genetic loss of expression of a minimal region of chromosome 15 encompassing the SNORD116 gene, encoding for a long noncoding RNA that plays a potential role in epigenetic regulation. Nevertheless, the role of the SNORD116 MD in DNA methylation, as well as the impact of OXT on it, have never been investigated in human neurons. Methods: We studied the methylation marks in dopaminergic neurons issued from induced pluripotent stem neuronsscells (iPSC) carrying a SNORD116 MD in comparison with those from an age-matched adult healthy control. We also performed identical neurons differentiation in the presence of OXT. We performed a genome-wide DNA methylation analysis from iPSC-derived dopaminergic neurons by reduced-representation bisulfite sequencing. In addition, we performed RNA sequencing analysis in the iPSC-derived dopaminergic neurons differentiated with or without OXT. Results: The analysis revealed that among the differentially methylated genes, we determined a list of gene also differentially expressed. Enrichment analysis of this list encompassed dopaminergic system with COMT and SLC6A3.RT-qPCR attested significant over expression of SLC6A3 in SNORD116 MD neuronss. Moreover, the expression of this gene was significantly decreased in case of OXT adjunction during the differentiation. . Conclusion: SNORD116 MD dopaminergic neurons display differential methylation and expression in genes related to dopaminergic clearance .

ORGANISM(S): Homo sapiens

PROVIDER: GSE249891 | GEO | 2024/05/07

REPOSITORIES: GEO

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Project description:Induced pluripotent stem cells (iPSCs) hold great promise for in vitro disease modeling and cell replacement therapy for Parkinson’s disease (PD). Both applications crucially require an in-depth profiling of the disease-relevant, iPSC-derived cell type. Midbrain dopaminergic (mDA) neurons derived from pluripotent stem cells are of substantial interest because of their instrumental value for PD therapy. IPSC-derived mDA neuron-like cells have been generated, however, detailed genetic and epigenetic characterization of strictly purified in vitro generated DA neurons has so far lagged behind. We generated mouse Pitx3gfp/+ iPSC-derived DA neurons that, after fluorescent activated cell sorting (FACS) allowed comprehensive comparison to mesodiencephalic dopaminergic (mdDA) neurons from Fac-sorted Pitx3gfp/+ ventral midbrains. We performed detailed analysis of global gene expression and genome-scale DNA methylation of CpG islands (CGIs) by reduced representation bisulfite sequencing. The reprogramming pathway from fibroblasts to iPSCs left parental cell footprints for both gene expression and DNA methylation. However, most gene expression patterns of iPSC-derived DA neurons closely resembled that of primary mdDA neurons with the strongest correlations for mdDA specific genes. Also, for DNA methylation patterns, high similarities were found for the vast majority of CGIs when comparing primary mdDA neurons with iPSC-derived DA neurons. Additionally, we found de novo DNA methylation during in vitro differentiation for hundreds of genes specifically in lineage-committed neural precursors that persisted in iPSC-derived DA neurons. Our study provides novel detailed characteristics of iPSC-derived DA neurons in comparison to the primary cell type. These findings add important information to our knowledge about these biomedically highly valuable, in vitro generated neurons. Microarray expression study comparing 3 samples of facs-sorted, Pitx3-gfp positive cells from each experimental group to a common reference consisting of adult mouse midbrain RNA. Each sample was analysed in normal and opposite dye orientation.

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RNA seq in IPSCs derived dopaminergic neurons comparison of SNORD116MD versus control

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