Epigenetic characterization of the FMR1 promoter in induced pluripotent stem cells from human fibroblasts carrying an unmethylated full mutation

Celine E F de Esch; Mehrnaz Ghazvini; Friedemann Loos; Nune Schelling-Kazaryan; W Widagdo; Shashini T Munshi; Erik van der Wal; Hannie Douben; Nilhan Gunhanlar; Steven A Kushner; W W M Pim Pijnappel; Femke M S de Vrij; Niels Geijsen; Joost Gribnau; Rob Willemsen

doi:10.1016/j.stemcr.2014.07.013

Epigenetic characterization of the FMR1 promoter in induced pluripotent stem cells from human fibroblasts carrying an unmethylated full mutation

Celine E F de Esch, Mehrnaz Ghazvini, Friedemann Loos, Nune Schelling-Kazaryan, W Widagdo, Shashini T Munshi, Erik van der Wal, Hannie Douben, Nilhan Gunhanlar, Steven A Kushner, W W M Pim Pijnappel, Femke M S de Vrij, Niels Geijsen, Joost Gribnau, Rob Willemsen

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

Abstract

Silencing of the FMR1 gene leads to fragile X syndrome, the most common cause of inherited intellectual disability. To study the epigenetic modifications of the FMR1 gene during silencing in time, we used fibroblasts and induced pluripotent stem cells (iPSCs) of an unmethylated full mutation (uFM) individual with normal intelligence. The uFM fibroblast line carried an unmethylated FMR1 promoter region and expressed normal to slightly increased FMR1 mRNA levels. The FMR1 expression in the uFM line corresponds with the increased H3 acetylation and H3K4 methylation in combination with a reduced H3K9 methylation. After reprogramming, the FMR1 promoter region was methylated in all uFM iPSC clones. Two clones were analyzed further and showed a lack of FMR1 expression, whereas the presence of specific histone modifications also indicated a repressed FMR1 promoter. In conclusion, these findings demonstrate that the standard reprogramming procedure leads to epigenetic silencing of the fully mutated FMR1 gene.

Original language	English
Pages (from-to)	548-55
Number of pages	8
Journal	Stem Cell Reports [E]
Volume	3
Issue number	4
DOIs	https://doi.org/10.1016/j.stemcr.2014.07.013
Publication status	Published - 2014

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de Esch, C. E. F., Ghazvini, M., Loos, F., Schelling-Kazaryan, N., Widagdo, W., Munshi, S. T., van der Wal, E., Douben, H., Gunhanlar, N., Kushner, S. A., Pijnappel, W. W. M. P., de Vrij, F. M. S., Geijsen, N., Gribnau, J., & Willemsen, R. (2014). Epigenetic characterization of the FMR1 promoter in induced pluripotent stem cells from human fibroblasts carrying an unmethylated full mutation. Stem Cell Reports [E], 3(4), 548-55. https://doi.org/10.1016/j.stemcr.2014.07.013

@article{a44c96074f21402b82dd7e5981a6f610,

title = "Epigenetic characterization of the FMR1 promoter in induced pluripotent stem cells from human fibroblasts carrying an unmethylated full mutation",

abstract = "Silencing of the FMR1 gene leads to fragile X syndrome, the most common cause of inherited intellectual disability. To study the epigenetic modifications of the FMR1 gene during silencing in time, we used fibroblasts and induced pluripotent stem cells (iPSCs) of an unmethylated full mutation (uFM) individual with normal intelligence. The uFM fibroblast line carried an unmethylated FMR1 promoter region and expressed normal to slightly increased FMR1 mRNA levels. The FMR1 expression in the uFM line corresponds with the increased H3 acetylation and H3K4 methylation in combination with a reduced H3K9 methylation. After reprogramming, the FMR1 promoter region was methylated in all uFM iPSC clones. Two clones were analyzed further and showed a lack of FMR1 expression, whereas the presence of specific histone modifications also indicated a repressed FMR1 promoter. In conclusion, these findings demonstrate that the standard reprogramming procedure leads to epigenetic silencing of the fully mutated FMR1 gene.",

author = "{de Esch}, {Celine E F} and Mehrnaz Ghazvini and Friedemann Loos and Nune Schelling-Kazaryan and W Widagdo and Munshi, {Shashini T} and {van der Wal}, Erik and Hannie Douben and Nilhan Gunhanlar and Kushner, {Steven A} and Pijnappel, {W W M Pim} and {de Vrij}, {Femke M S} and Niels Geijsen and Joost Gribnau and Rob Willemsen",

year = "2014",

doi = "10.1016/j.stemcr.2014.07.013",

language = "English",

volume = "3",

pages = "548--55",

journal = "Stem Cell Reports [E]",

issn = "2213-6711",

publisher = "Cell Press",

number = "4",

}

de Esch, CEF, Ghazvini, M, Loos, F, Schelling-Kazaryan, N, Widagdo, W, Munshi, ST, van der Wal, E, Douben, H, Gunhanlar, N, Kushner, SA, Pijnappel, WWMP, de Vrij, FMS, Geijsen, N, Gribnau, J & Willemsen, R 2014, 'Epigenetic characterization of the FMR1 promoter in induced pluripotent stem cells from human fibroblasts carrying an unmethylated full mutation', Stem Cell Reports [E], vol. 3, no. 4, pp. 548-55. https://doi.org/10.1016/j.stemcr.2014.07.013

TY - JOUR

T1 - Epigenetic characterization of the FMR1 promoter in induced pluripotent stem cells from human fibroblasts carrying an unmethylated full mutation

AU - de Esch, Celine E F

AU - Ghazvini, Mehrnaz

AU - Loos, Friedemann

AU - Schelling-Kazaryan, Nune

AU - Widagdo, W

AU - Munshi, Shashini T

AU - van der Wal, Erik

AU - Douben, Hannie

AU - Gunhanlar, Nilhan

AU - Kushner, Steven A

AU - Pijnappel, W W M Pim

AU - de Vrij, Femke M S

AU - Geijsen, Niels

AU - Gribnau, Joost

AU - Willemsen, Rob

PY - 2014

Y1 - 2014

N2 - Silencing of the FMR1 gene leads to fragile X syndrome, the most common cause of inherited intellectual disability. To study the epigenetic modifications of the FMR1 gene during silencing in time, we used fibroblasts and induced pluripotent stem cells (iPSCs) of an unmethylated full mutation (uFM) individual with normal intelligence. The uFM fibroblast line carried an unmethylated FMR1 promoter region and expressed normal to slightly increased FMR1 mRNA levels. The FMR1 expression in the uFM line corresponds with the increased H3 acetylation and H3K4 methylation in combination with a reduced H3K9 methylation. After reprogramming, the FMR1 promoter region was methylated in all uFM iPSC clones. Two clones were analyzed further and showed a lack of FMR1 expression, whereas the presence of specific histone modifications also indicated a repressed FMR1 promoter. In conclusion, these findings demonstrate that the standard reprogramming procedure leads to epigenetic silencing of the fully mutated FMR1 gene.

AB - Silencing of the FMR1 gene leads to fragile X syndrome, the most common cause of inherited intellectual disability. To study the epigenetic modifications of the FMR1 gene during silencing in time, we used fibroblasts and induced pluripotent stem cells (iPSCs) of an unmethylated full mutation (uFM) individual with normal intelligence. The uFM fibroblast line carried an unmethylated FMR1 promoter region and expressed normal to slightly increased FMR1 mRNA levels. The FMR1 expression in the uFM line corresponds with the increased H3 acetylation and H3K4 methylation in combination with a reduced H3K9 methylation. After reprogramming, the FMR1 promoter region was methylated in all uFM iPSC clones. Two clones were analyzed further and showed a lack of FMR1 expression, whereas the presence of specific histone modifications also indicated a repressed FMR1 promoter. In conclusion, these findings demonstrate that the standard reprogramming procedure leads to epigenetic silencing of the fully mutated FMR1 gene.

U2 - 10.1016/j.stemcr.2014.07.013

DO - 10.1016/j.stemcr.2014.07.013

M3 - Article

C2 - 25358783

SN - 2213-6711

VL - 3

SP - 548

EP - 555

JO - Stem Cell Reports [E]

JF - Stem Cell Reports [E]

IS - 4

ER -

Epigenetic characterization of the FMR1 promoter in induced pluripotent stem cells from human fibroblasts carrying an unmethylated full mutation

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