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CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations
In fragile X syndrome (FXS), CGG repeat expansion greater than 200 triplets is believed to trigger FMR1 gene silencing and disease etiology. However, FXS siblings have been identified with more than 200 CGGs, termed unmethylated full mutation (UFM) carriers, without gene silencing and disease sympto...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161530/ https://www.ncbi.nlm.nih.gov/pubmed/27840045 http://dx.doi.org/10.1016/j.stemcr.2016.10.004 |
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author | Brykczynska, Urszula Pecho-Vrieseling, Eline Thiemeyer, Anke Klein, Jessica Fruh, Isabelle Doll, Thierry Manneville, Carole Fuchs, Sascha Iazeolla, Mariavittoria Beibel, Martin Roma, Guglielmo Naumann, Ulrike Kelley, Nicholas Oakeley, Edward J. Mueller, Matthias Gomez-Mancilla, Baltazar Bühler, Marc Tabolacci, Elisabetta Chiurazzi, Pietro Neri, Giovanni Bouwmeester, Tewis Di Giorgio, Francesco Paolo Fodor, Barna D. |
author_facet | Brykczynska, Urszula Pecho-Vrieseling, Eline Thiemeyer, Anke Klein, Jessica Fruh, Isabelle Doll, Thierry Manneville, Carole Fuchs, Sascha Iazeolla, Mariavittoria Beibel, Martin Roma, Guglielmo Naumann, Ulrike Kelley, Nicholas Oakeley, Edward J. Mueller, Matthias Gomez-Mancilla, Baltazar Bühler, Marc Tabolacci, Elisabetta Chiurazzi, Pietro Neri, Giovanni Bouwmeester, Tewis Di Giorgio, Francesco Paolo Fodor, Barna D. |
author_sort | Brykczynska, Urszula |
collection | PubMed |
description | In fragile X syndrome (FXS), CGG repeat expansion greater than 200 triplets is believed to trigger FMR1 gene silencing and disease etiology. However, FXS siblings have been identified with more than 200 CGGs, termed unmethylated full mutation (UFM) carriers, without gene silencing and disease symptoms. Here, we show that hypomethylation of the FMR1 promoter is maintained in induced pluripotent stem cells (iPSCs) derived from two UFM individuals. However, a subset of iPSC clones with large CGG expansions carries silenced FMR1. Furthermore, we demonstrate de novo silencing upon expansion of the CGG repeat size. FMR1 does not undergo silencing during neuronal differentiation of UFM iPSCs, and expression of large unmethylated CGG repeats has phenotypic consequences resulting in neurodegenerative features. Our data suggest that UFM individuals do not lack the cell-intrinsic ability to silence FMR1 and that inter-individual variability in the CGG repeat size required for silencing exists in the FXS population. |
format | Online Article Text |
id | pubmed-5161530 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-51615302016-12-21 CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations Brykczynska, Urszula Pecho-Vrieseling, Eline Thiemeyer, Anke Klein, Jessica Fruh, Isabelle Doll, Thierry Manneville, Carole Fuchs, Sascha Iazeolla, Mariavittoria Beibel, Martin Roma, Guglielmo Naumann, Ulrike Kelley, Nicholas Oakeley, Edward J. Mueller, Matthias Gomez-Mancilla, Baltazar Bühler, Marc Tabolacci, Elisabetta Chiurazzi, Pietro Neri, Giovanni Bouwmeester, Tewis Di Giorgio, Francesco Paolo Fodor, Barna D. Stem Cell Reports Article In fragile X syndrome (FXS), CGG repeat expansion greater than 200 triplets is believed to trigger FMR1 gene silencing and disease etiology. However, FXS siblings have been identified with more than 200 CGGs, termed unmethylated full mutation (UFM) carriers, without gene silencing and disease symptoms. Here, we show that hypomethylation of the FMR1 promoter is maintained in induced pluripotent stem cells (iPSCs) derived from two UFM individuals. However, a subset of iPSC clones with large CGG expansions carries silenced FMR1. Furthermore, we demonstrate de novo silencing upon expansion of the CGG repeat size. FMR1 does not undergo silencing during neuronal differentiation of UFM iPSCs, and expression of large unmethylated CGG repeats has phenotypic consequences resulting in neurodegenerative features. Our data suggest that UFM individuals do not lack the cell-intrinsic ability to silence FMR1 and that inter-individual variability in the CGG repeat size required for silencing exists in the FXS population. Elsevier 2016-11-10 /pmc/articles/PMC5161530/ /pubmed/27840045 http://dx.doi.org/10.1016/j.stemcr.2016.10.004 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Brykczynska, Urszula Pecho-Vrieseling, Eline Thiemeyer, Anke Klein, Jessica Fruh, Isabelle Doll, Thierry Manneville, Carole Fuchs, Sascha Iazeolla, Mariavittoria Beibel, Martin Roma, Guglielmo Naumann, Ulrike Kelley, Nicholas Oakeley, Edward J. Mueller, Matthias Gomez-Mancilla, Baltazar Bühler, Marc Tabolacci, Elisabetta Chiurazzi, Pietro Neri, Giovanni Bouwmeester, Tewis Di Giorgio, Francesco Paolo Fodor, Barna D. CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations |
title | CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations |
title_full | CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations |
title_fullStr | CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations |
title_full_unstemmed | CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations |
title_short | CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations |
title_sort | cgg repeat-induced fmr1 silencing depends on the expansion size in human ipscs and neurons carrying unmethylated full mutations |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161530/ https://www.ncbi.nlm.nih.gov/pubmed/27840045 http://dx.doi.org/10.1016/j.stemcr.2016.10.004 |
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