Epigenetic Characterization of the FMR1 Promoter in Induced Pluripotent Stem Cells from Human Fibroblasts Carrying an Unmethylated Full Mutation

被引:44
|
作者
de Esch, Celine E. F. [1 ]
Ghazvini, Mehrnaz [2 ,3 ]
Loos, Friedemann [3 ]
Schelling-Kazaryan, Nune [4 ,5 ]
Widagdo, W. [1 ]
Munshi, Shashini T. [6 ]
van der Wal, Erik [7 ,8 ]
Douben, Hannie [1 ]
Gunhanlar, Nilhan [6 ]
Kushner, Steven A. [6 ]
Pijnappel, W. W. M. Pim [7 ,8 ]
de Vrij, Femke M. S. [6 ]
Geijsen, Niels [4 ,5 ,9 ]
Gribnau, Joost [3 ]
Willemsen, Rob [1 ]
机构
[1] Erasmus MC, Dept Clin Genet, NL-3015 GE Rotterdam, Netherlands
[2] Erasmus MC, iPS Cell Facil, NL-3015 GE Rotterdam, Netherlands
[3] Erasmus MC, Dept Reprod & Dev, NL-3015 GE Rotterdam, Netherlands
[4] KNAW Hubrecht Inst, NL-3584 CT Utrecht, Netherlands
[5] UMC Utrecht, NL-3584 CT Utrecht, Netherlands
[6] Erasmus MC, Dept Psychiat, NL-3015 GE Rotterdam, Netherlands
[7] Erasmus MC, Ctr Lysosomal & Metab Dis, Dept Clin Genet, NL-3015 GE Rotterdam, Netherlands
[8] Erasmus MC, Ctr Lysosomal & Metab Dis, Dept Pediat, Div Metab Dis & Genet, NL-3015 GE Rotterdam, Netherlands
[9] Univ Utrecht, Sch Vet Med, Dept Compan Anim, NL-3508 TD Utrecht, Netherlands
来源
STEM CELL REPORTS | 2014年 / 3卷 / 04期
关键词
FRAGILE-X-SYNDROME; GENE; REACTIVATION;
D O I
10.1016/j.stemcr.2014.07.013
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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.
引用
收藏
页码:548 / 555
页数:8
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