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Stem Cell Reports. 2014 Oct 14;3(4):548-55. doi: 10.1016/j.stemcr.2014.07.013. Epub 2014 Sep 11.

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

Author information

1
Department of Clinical Genetics, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
2
iPS Cell Facility, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands; Department of Reproduction and Development, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
3
Department of Reproduction and Development, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
4
KNAW Hubrecht Institute and UMC Utrecht, 3584 CT Utrecht, the Netherlands.
5
Department of Psychiatry, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
6
Molecular Stem Cell Biology, Department of Clinical Genetics and Department of Pediatrics, Division of Metabolic Diseases and Genetics, Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
7
KNAW Hubrecht Institute and UMC Utrecht, 3584 CT Utrecht, the Netherlands; Department Companion Animals, Utrecht University School for Veterinary Medicine, 3508 TD Utrecht, the Netherlands.
8
Department of Clinical Genetics, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands. Electronic address: r.willemsen@erasmusmc.nl.

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.

PMID:
25358783
PMCID:
PMC4223701
DOI:
10.1016/j.stemcr.2014.07.013
[Indexed for MEDLINE]
Free PMC Article

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