Reversion of FMR1 methylation and silencing by editing the triplet repeats in Fragile X iPSC-derived neurons
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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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The mutation-length CGG STR acquires DNA methylation, which is thought to cause FMR1 silencing.
“The mutation-length CGG STR acquires DNA methylation, which is thought to cause FMR1 silencing (Park et al., 2015).”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Park et al., 2015
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Self-citation
- Authors
- Park, C.-Y., Halevy, T., Lee, D. R., Sung, J. J., Lee, J. S., Yanuka, O., Benvenisty, N., & Kim, D.-W.
- Affiliations
- Yonsei University (KR)
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Benvenisty, Nissim
- Kim, Dong-Wook
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 13
- Issue
- 2
- Pages
- 234-241
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2121389760
- Cited by
- 178
- References
- 42
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 9 · 2023: 12 · 2022: 11 · 2021: 20 · 2020: 19 · 2019: 24 · 2018: 34 · 2017: 17 · 2016: 18 · 2015: 3
- FWCI
- 16.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Rosetrees Trust (M108-F1)
- National Research Foundation
- Yonsei University
- National Research Foundation of Korea (2012M3A9B4028631, 2012M3A9C7050126)
- Azrieli Foundation
- Yonsei University College of Medicine
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- fragile X syndrome, FMR1 gene, CGG repeat expansion, CRISPR/Cas9 genome editing, induced pluripotent stem cells, embryonic stem cells, iPSC-derived neurons, DNA methylation, promoter silencing, CpG island demethylation, trinucleotide repeat disorders, intellectual disability
- MeSH terms
- Cells, Cultured, Fragile X Syndrome, Humans, Neurons, Promoter Regions, Genetic, CpG Islands, Trinucleotide Repeats, DNA Methylation, Gene Silencing, Fragile X Messenger Ribonucleoprotein 1, Induced Pluripotent Stem Cells, CRISPR-Cas Systems
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