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

1 Citation (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

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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.",

author = "Karen Gr{\"u}tz and Philip Seibler and Anne Weissbach and Katja Lohmann and Carlisle, {Francesca A.} and Blake, {Derek J.} and Ana Westenberger and Christine Klein and Anne Gr{\"u}newald",

year = "2017",

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doi = "10.1038/srep41156",

language = "English",

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T1 - Faithful SGCE imprinting in iPSC-derived cortical neurons: An endogenous cellular model of myoclonus-dystonia

AU - Grütz, Karen

AU - Seibler, Philip

AU - Weissbach, Anne

AU - Lohmann, Katja

AU - Carlisle, Francesca A.

AU - Blake, Derek J.

AU - Westenberger, Ana

AU - Klein, Christine

AU - Grünewald, Anne

PY - 2017/2/3

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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M3 - Journal articles

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SN - 2045-2322

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JO - Scientific Reports

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

Abstract

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