Marked Differences in C9orf72 Methylation Status and Isoform Expression between C9/ALS Human Embryonic and Induced Pluripotent Stem Cells

Yaara Cohen-Hadad; Gheona Altarescu; Talia Eldar-Geva; Ephrat Levi-Lahad; Ming Zhang; Ekaterina Rogaeva; Marc Gotkine; Osnat Bartok; Reut Ashwal-Fluss; Sebastian Kadener; Silvina Epsztejn-Litman; Rachel Eiges

doi:10.1016/j.stemcr.2016.09.011

Marked Differences in C9orf72 Methylation Status and Isoform Expression between C9/ALS Human Embryonic and Induced Pluripotent Stem Cells

Yaara Cohen-Hadad, Gheona Altarescu, Talia Eldar-Geva, Ephrat Levi-Lahad, Ming Zhang, Ekaterina Rogaeva, Marc Gotkine, Osnat Bartok, Reut Ashwal-Fluss, Sebastian Kadener, Silvina Epsztejn-Litman, Rachel Eiges^*

^*Corresponding author for this work

Institute for Medical Research Israel-Canada (IMRIC)

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

We established two human embryonic stem cell (hESC) lines with a GGGGCC expansion in the C9orf72 gene (C9), and compared them with haploidentical and unrelated C9 induced pluripotent stem cells (iPSCs). We found a marked difference in C9 methylation between the cells. hESCs and parental fibroblasts are entirely unmethylated while the iPSCs are hypermethylated. In addition, we show that the expansion alters promoter usage and interferes with the proper splicing of intron 1, eventually leading to the accumulation of repeat-containing mRNA following neural differentiation. These changes are attenuated in C9 iPSCs, presumably owing to hypermethylation. Altogether, this study highlights the importance of neural differentiation in the pathogenesis of disease and points to the potential role of hypermethylation as a neuroprotective mechanism against pathogenic mRNAs, envisaging a milder phenotype in C9 iPSCs.

Original language	English
Pages (from-to)	927-940
Number of pages	14
Journal	Stem Cell Reports
Volume	7
Issue number	5
DOIs	https://doi.org/10.1016/j.stemcr.2016.09.011
State	Published - 8 Nov 2016

Bibliographical note

Publisher Copyright:
© 2016 The Authors

Keywords

C9/ALS
CpG islands
DNA methylation
disease modelling
neurodegeneration
pluripotent stem cells
unstable repeat expansions

Access to Document

10.1016/j.stemcr.2016.09.011

Cite this

Cohen-Hadad, Y., Altarescu, G., Eldar-Geva, T., Levi-Lahad, E., Zhang, M., Rogaeva, E., Gotkine, M., Bartok, O., Ashwal-Fluss, R., Kadener, S., Epsztejn-Litman, S., & Eiges, R. (2016). Marked Differences in C9orf72 Methylation Status and Isoform Expression between C9/ALS Human Embryonic and Induced Pluripotent Stem Cells. Stem Cell Reports, 7(5), 927-940. https://doi.org/10.1016/j.stemcr.2016.09.011

@article{ef42813d6095469fa73eed593bb175c9,

title = "Marked Differences in C9orf72 Methylation Status and Isoform Expression between C9/ALS Human Embryonic and Induced Pluripotent Stem Cells",

abstract = "We established two human embryonic stem cell (hESC) lines with a GGGGCC expansion in the C9orf72 gene (C9), and compared them with haploidentical and unrelated C9 induced pluripotent stem cells (iPSCs). We found a marked difference in C9 methylation between the cells. hESCs and parental fibroblasts are entirely unmethylated while the iPSCs are hypermethylated. In addition, we show that the expansion alters promoter usage and interferes with the proper splicing of intron 1, eventually leading to the accumulation of repeat-containing mRNA following neural differentiation. These changes are attenuated in C9 iPSCs, presumably owing to hypermethylation. Altogether, this study highlights the importance of neural differentiation in the pathogenesis of disease and points to the potential role of hypermethylation as a neuroprotective mechanism against pathogenic mRNAs, envisaging a milder phenotype in C9 iPSCs.",

keywords = "C9/ALS, CpG islands, DNA methylation, disease modelling, neurodegeneration, pluripotent stem cells, unstable repeat expansions",

author = "Yaara Cohen-Hadad and Gheona Altarescu and Talia Eldar-Geva and Ephrat Levi-Lahad and Ming Zhang and Ekaterina Rogaeva and Marc Gotkine and Osnat Bartok and Reut Ashwal-Fluss and Sebastian Kadener and Silvina Epsztejn-Litman and Rachel Eiges",

note = "Publisher Copyright: {\textcopyright} 2016 The Authors",

year = "2016",

month = nov,

day = "8",

doi = "10.1016/j.stemcr.2016.09.011",

language = "אנגלית",

volume = "7",

pages = "927--940",

journal = "Stem Cell Reports",

issn = "2213-6711",

publisher = "Cell Press",

number = "5",

}

Cohen-Hadad, Y, Altarescu, G, Eldar-Geva, T, Levi-Lahad, E, Zhang, M, Rogaeva, E, Gotkine, M, Bartok, O, Ashwal-Fluss, R, Kadener, S, Epsztejn-Litman, S & Eiges, R 2016, 'Marked Differences in C9orf72 Methylation Status and Isoform Expression between C9/ALS Human Embryonic and Induced Pluripotent Stem Cells', Stem Cell Reports, vol. 7, no. 5, pp. 927-940. https://doi.org/10.1016/j.stemcr.2016.09.011

TY - JOUR

T1 - Marked Differences in C9orf72 Methylation Status and Isoform Expression between C9/ALS Human Embryonic and Induced Pluripotent Stem Cells

AU - Cohen-Hadad, Yaara

AU - Altarescu, Gheona

AU - Eldar-Geva, Talia

AU - Levi-Lahad, Ephrat

AU - Zhang, Ming

AU - Rogaeva, Ekaterina

AU - Gotkine, Marc

AU - Bartok, Osnat

AU - Ashwal-Fluss, Reut

AU - Kadener, Sebastian

AU - Epsztejn-Litman, Silvina

AU - Eiges, Rachel

PY - 2016/11/8

Y1 - 2016/11/8

N2 - We established two human embryonic stem cell (hESC) lines with a GGGGCC expansion in the C9orf72 gene (C9), and compared them with haploidentical and unrelated C9 induced pluripotent stem cells (iPSCs). We found a marked difference in C9 methylation between the cells. hESCs and parental fibroblasts are entirely unmethylated while the iPSCs are hypermethylated. In addition, we show that the expansion alters promoter usage and interferes with the proper splicing of intron 1, eventually leading to the accumulation of repeat-containing mRNA following neural differentiation. These changes are attenuated in C9 iPSCs, presumably owing to hypermethylation. Altogether, this study highlights the importance of neural differentiation in the pathogenesis of disease and points to the potential role of hypermethylation as a neuroprotective mechanism against pathogenic mRNAs, envisaging a milder phenotype in C9 iPSCs.

AB - We established two human embryonic stem cell (hESC) lines with a GGGGCC expansion in the C9orf72 gene (C9), and compared them with haploidentical and unrelated C9 induced pluripotent stem cells (iPSCs). We found a marked difference in C9 methylation between the cells. hESCs and parental fibroblasts are entirely unmethylated while the iPSCs are hypermethylated. In addition, we show that the expansion alters promoter usage and interferes with the proper splicing of intron 1, eventually leading to the accumulation of repeat-containing mRNA following neural differentiation. These changes are attenuated in C9 iPSCs, presumably owing to hypermethylation. Altogether, this study highlights the importance of neural differentiation in the pathogenesis of disease and points to the potential role of hypermethylation as a neuroprotective mechanism against pathogenic mRNAs, envisaging a milder phenotype in C9 iPSCs.

KW - C9/ALS

KW - CpG islands

KW - DNA methylation

KW - disease modelling

KW - neurodegeneration

KW - pluripotent stem cells

KW - unstable repeat expansions

UR - http://www.scopus.com/inward/record.url?scp=84994627664&partnerID=8YFLogxK

U2 - 10.1016/j.stemcr.2016.09.011

DO - 10.1016/j.stemcr.2016.09.011

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 27773700

AN - SCOPUS:84994627664

SN - 2213-6711

VL - 7

SP - 927

EP - 940

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 5

ER -

Marked Differences in C9orf72 Methylation Status and Isoform Expression between C9/ALS Human Embryonic and Induced Pluripotent Stem Cells

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Cite this