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.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Celine E F
authors.initials: CE
authors.lastname: de Esch
authors.affiliation: iPS Cell Facility, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands; Department of Reproduction and Development, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Ghazvini
authors.affiliation: Department of Reproduction and Development, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Loos
authors.affiliation: KNAW Hubrecht Institute and UMC Utrecht, 3584 CT Utrecht, the Netherlands.
authors.forename: Nune
authors.initials: N
authors.lastname: Schelling-Kazaryan
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Widagdo
authors.affiliation: Department of Psychiatry, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Shashini T
authors.initials: ST
authors.lastname: Munshi
authors.affiliation: 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.
authors.forename: Erik
authors.initials: E
authors.lastname: van der Wal
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Hannie
authors.initials: H
authors.lastname: Douben
authors.affiliation: Department of Psychiatry, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Nilhan
authors.initials: N
authors.lastname: Gunhanlar
authors.affiliation: Department of Psychiatry, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kushner
authors.affiliation: 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.
authors.forename: W W M Pim
authors.initials: WW
authors.lastname: Pijnappel
authors.affiliation: Department of Psychiatry, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Femke M S
authors.initials: FM
authors.lastname: de Vrij
authors.affiliation: 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.
authors.forename: Niels
authors.initials: N
authors.lastname: Geijsen
authors.affiliation: Department of Reproduction and Development, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Gribnau
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands. Electronic address: r.willemsen@erasmusmc.nl.
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
mesh_terms: D000293:Adolescent; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D065150:Cellular Reprogramming; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D006657:Histones; D012333:RNA, Messenger; C497683:FMR1 protein, human