Reversion of FMR1 Methylation and Silencing by Editing the Triplet Repeats in Fragile X iPSC-Derived Neurons
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| Název: | Reversion of FMR1 Methylation and Silencing by Editing the Triplet Repeats in Fragile X iPSC-Derived Neurons |
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| Autoři: | Jae Souk Lee, Tomer Halevy, Dong-Wook Kim, Ofra Yanuka, Nissim Benvenisty, Jin Jea Sung, Chul-Yong Park, Dongjin R. Lee |
| Přispěvatelé: | Chul-Yong Park, Tomer Halevy, Dongjin R. Lee, Jin Jea Sung, Jae Souk Lee, Ofra Yanuka, Nissim Benvenisty, Dong-Wook Kim, Kim, Dong Wook, Park, Chul Yong |
| Zdroj: | Cell Reports, Vol 13, Iss 2, Pp 234-241 (2015) |
| Informace o vydavateli: | Elsevier BV, 2015. |
| Rok vydání: | 2015 |
| Témata: | 0301 basic medicine, QH301-705.5, Cells, Induced Pluripotent Stem Cells, Induced Pluripotent Stem Cells/metabolism, Promoter Regions, Neurons/cytology, Fragile X Mental Retardation Protein, 03 medical and health sciences, Induced Pluripotent Stem Cells/cytology, Genetic, Trinucleotide Repeats, Humans, Gene Silencing, Biology (General), Promoter Regions, Genetic, Cells, Cultured, Neurons/metabolism, Neurons, DNA Methylation, 0303 health sciences, Cultured, Fragile X Syndrome/genetics, Fragile X Mental Retardation Protein/metabolism, Fragile X Mental Retardation Protein/genetics, Fragile X Syndrome, CpG Islands, CRISPR-Cas Systems |
| Popis: | 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. |
| Druh dokumentu: | Article |
| Popis souboru: | 234~241 |
| Jazyk: | English |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2015.08.084 |
| Přístupová URL adresa: | http://www.cell.com/article/S2211124715010098/pdf https://pubmed.ncbi.nlm.nih.gov/26440889 https://doaj.org/article/39333aed95a7441eb157a164decfd490 http://www.cell.com/cell-reports/pdf/S2211-1247(15)01009-8.pdf https://www.ncbi.nlm.nih.gov/pubmed/26440889 https://pubmed.ncbi.nlm.nih.gov/26440889/ https://www.infona.pl/resource/bwmeta1.element.elsevier-c8ef21c7-c530-3062-ac2e-a7185f28ee42 https://www.cell.com/cell-reports/abstract/S2211-1247(15)01009-8 https://www.cell.com/cell-reports/pdf/S2211-1247(15)01009-8.pdf |
| Rights: | CC BY NC ND |
| Přístupové číslo: | edsair.doi.dedup.....8316f2bf0faf44e4ee9454d8b83a6a8b |
| Databáze: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | 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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| ISSN: | 22111247 |
| DOI: | 10.1016/j.celrep.2015.08.084 |