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/periodicalArticleScientificpeer-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 languageEnglish
Pages (from-to)548-55
Number of pages8
JournalStem Cell Reports
Volume3
Issue number4
DOIs
Publication statusPublished - 14 Oct 2014

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