Faithful SGCE imprinting in iPSC-derived cortical neurons: An endogenous cellular model of myoclonus-dystonia

Karen Grütz; Philip Seibler; Anne Weissbach; Katja Lohmann; Francesca A. Carlisle; Derek J. Blake; Ana Westenberger; Christine Klein; Anne Grünewald

doi:10.1038/srep41156

Faithful SGCE imprinting in iPSC-derived cortical neurons: An endogenous cellular model of myoclonus-dystonia

Karen Grütz, Philip Seibler, Anne Weissbach, Katja Lohmann, Francesca A. Carlisle, Derek J. Blake, Ana Westenberger, Christine Klein^*, Anne Grünewald

^*Corresponding author for this work

18 Citations (Scopus)

Abstract

In neuropathology research, induced pluripotent stem cell (iPSC)-derived neurons are considered a tool closely resembling the patient brain. Albeit in respect to epigenetics, this concept has been challenged. We generated iPSC-derived cortical neurons from myoclonus-dystonia patients with mutations (W100G and R102X) in the maternally imprinted ϵ-sarcoglycan (SGCE) gene and analysed properties such as imprinting, mRNA and protein expression. Comparison of the promoter during reprogramming and differentiation showed tissue-independent differential methylation. DNA sequencing with methylation-specific primers and cDNA analysis in patient neurons indicated selective expression of the mutated paternal SGCE allele. While fibroblasts only expressed the ubiquitous mRNA isoform, brain-specific SGCE mRNA and ϵ-sarcoglycan protein were detected in iPSC-derived control neurons. However, neuronal protein levels were reduced in both mutants. Our phenotypic characterization highlights the suitability of iPSC-derived cortical neurons with SGCE mutations for myoclonus-dystonia research and, in more general terms, prompts the use of iPSC-derived cellular models to study epigenetic mechanisms impacting on health and disease.

Original language	English
Article number	41156
Journal	Scientific Reports
Volume	7
ISSN	2045-2322
DOIs	https://doi.org/10.1038/srep41156
Publication status	Published - 03.02.2017

Funding

This work was supported by the Dystonia Medical Research Foundation. We would like to acknowledge G. Gillessen-Kaesbach for supporting the iPSC characterization by karyotype analysis. Christine Klein receives a career development award from the Hermann and Lilly Schilling Foundation. Anne Gr?newald is the recipient of an ATTRACT career development grant from the National Research Fund Luxembourg (FNR).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 10 Reduced Inequalities

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title = "Faithful SGCE imprinting in iPSC-derived cortical neurons: An endogenous cellular model of myoclonus-dystonia",

abstract = "In neuropathology research, induced pluripotent stem cell (iPSC)-derived neurons are considered a tool closely resembling the patient brain. Albeit in respect to epigenetics, this concept has been challenged. We generated iPSC-derived cortical neurons from myoclonus-dystonia patients with mutations (W100G and R102X) in the maternally imprinted ϵ-sarcoglycan (SGCE) gene and analysed properties such as imprinting, mRNA and protein expression. Comparison of the promoter during reprogramming and differentiation showed tissue-independent differential methylation. DNA sequencing with methylation-specific primers and cDNA analysis in patient neurons indicated selective expression of the mutated paternal SGCE allele. While fibroblasts only expressed the ubiquitous mRNA isoform, brain-specific SGCE mRNA and ϵ-sarcoglycan protein were detected in iPSC-derived control neurons. However, neuronal protein levels were reduced in both mutants. Our phenotypic characterization highlights the suitability of iPSC-derived cortical neurons with SGCE mutations for myoclonus-dystonia research and, in more general terms, prompts the use of iPSC-derived cellular models to study epigenetic mechanisms impacting on health and disease.",

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AU - Grütz, Karen

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AU - Lohmann, Katja

AU - Carlisle, Francesca A.

AU - Blake, Derek J.

AU - Westenberger, Ana

AU - Klein, Christine

AU - Grünewald, Anne

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Y1 - 2017/2/3

N2 - In neuropathology research, induced pluripotent stem cell (iPSC)-derived neurons are considered a tool closely resembling the patient brain. Albeit in respect to epigenetics, this concept has been challenged. We generated iPSC-derived cortical neurons from myoclonus-dystonia patients with mutations (W100G and R102X) in the maternally imprinted ϵ-sarcoglycan (SGCE) gene and analysed properties such as imprinting, mRNA and protein expression. Comparison of the promoter during reprogramming and differentiation showed tissue-independent differential methylation. DNA sequencing with methylation-specific primers and cDNA analysis in patient neurons indicated selective expression of the mutated paternal SGCE allele. While fibroblasts only expressed the ubiquitous mRNA isoform, brain-specific SGCE mRNA and ϵ-sarcoglycan protein were detected in iPSC-derived control neurons. However, neuronal protein levels were reduced in both mutants. Our phenotypic characterization highlights the suitability of iPSC-derived cortical neurons with SGCE mutations for myoclonus-dystonia research and, in more general terms, prompts the use of iPSC-derived cellular models to study epigenetic mechanisms impacting on health and disease.

AB - In neuropathology research, induced pluripotent stem cell (iPSC)-derived neurons are considered a tool closely resembling the patient brain. Albeit in respect to epigenetics, this concept has been challenged. We generated iPSC-derived cortical neurons from myoclonus-dystonia patients with mutations (W100G and R102X) in the maternally imprinted ϵ-sarcoglycan (SGCE) gene and analysed properties such as imprinting, mRNA and protein expression. Comparison of the promoter during reprogramming and differentiation showed tissue-independent differential methylation. DNA sequencing with methylation-specific primers and cDNA analysis in patient neurons indicated selective expression of the mutated paternal SGCE allele. While fibroblasts only expressed the ubiquitous mRNA isoform, brain-specific SGCE mRNA and ϵ-sarcoglycan protein were detected in iPSC-derived control neurons. However, neuronal protein levels were reduced in both mutants. Our phenotypic characterization highlights the suitability of iPSC-derived cortical neurons with SGCE mutations for myoclonus-dystonia research and, in more general terms, prompts the use of iPSC-derived cellular models to study epigenetic mechanisms impacting on health and disease.

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Faithful SGCE imprinting in iPSC-derived cortical neurons: An endogenous cellular model of myoclonus-dystonia

Abstract

Funding

UN SDGs

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