Reversion of FMR1 Methylation and Silencing by Editing the Triplet Repeats in Fragile X iPSC-Derived Neurons.
Cell Rep
; 13(2): 234-41, 2015 Oct 13.
Article
em En
| MEDLINE
| ID: mdl-26440889
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Repetições de Trinucleotídeos
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Metilação de DNA
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Inativação Gênica
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Proteína do X Frágil da Deficiência Intelectual
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Células-Tronco Pluripotentes Induzidas
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Síndrome do Cromossomo X Frágil
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Neurônios
Limite:
Humans
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2015
Tipo de documento:
Article