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

Authors
 Chul-Yong Park  ;  Tomer Halevy  ;  Dongjin R. Lee  ;  Jin Jea Sung  ;  Jae Souk Lee  ;  Ofra Yanuka  ;  Nissim Benvenisty  ;  Dong-Wook Kim 
Citation
 Cell Reports, Vol.13(2) : 234-241, 2015 
Journal Title
 Cell Reports 
ISSN
 2211-1247 
Issue Date
2015
Abstract
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.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/141555
DOI
10.1016/j.celrep.2015.08.084
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실)
Yonsei Authors
김동욱(Kim, Dong Wook)
박철용(Park, Chul Yong)
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