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Reversion of FMR1 Methylation and Silencing by Editing the Triplet Repeats in Fragile X iPSC-Derived Neurons

 Chul-Yong Park  ;  Tomer Halevy  ;  Dongjin R. Lee  ;  Jin Jea Sung  ;  Jae Souk Lee  ;  Ofra Yanuka  ;  Nissim Benvenisty  ;  Dong-Wook Kim 
 CELL REPORTS, Vol.13(2) : 234-241, 2015 
Journal Title
Issue Date
CRISPR-Cas Systems ; Cells, Cultured ; CpG Islands ; DNA Methylation* ; Fragile X Mental Retardation Protein/genetics* ; Fragile X Mental Retardation Protein/metabolism ; Fragile X Syndrome/genetics* ; Gene Silencing* ; Humans ; Induced Pluripotent Stem Cells/cytology ; Induced Pluripotent Stem Cells/metabolism* ; Neurons/cytology ; Neurons/metabolism* ; Promoter Regions, Genetic ; Trinucleotide Repeats*
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability, resulting from a CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Here, we report a strategy for CGG repeat correction using CRISPR/Cas9 for targeted deletion in both embryonic stem cells and induced pluripotent stem cells derived from FXS patients. Following gene correction in FXS induced pluripotent stem cells, FMR1 expression was restored and sustained in neural precursor cells and mature neurons. Strikingly, after removal of the CGG repeats, the upstream CpG island of the FMR1 promoter showed extensive demethylation, an open chromatin state, and transcription initiation. These results suggest a silencing maintenance mechanism for the FMR1 promoter that is dependent on the existence of the CGG repeat expansion. Our strategy for deletion of trinucleotide repeats provides further insights into the molecular mechanisms of FXS and future therapies of trinucleotide repeat disorders.
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1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Dong Wook(김동욱) ORCID logo https://orcid.org/0000-0002-5025-1532
Park, Chul Yong(박철용) ORCID logo https://orcid.org/0000-0002-4467-9268
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