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.

Brykczynska, U., Pecho Vrieseling, E., Thiemeyer, A., Klein, J., Fruh, I., Doll, T., Manneville, C., Fuchs, S., Iazeolla, M., Beibel, M., Roma, G., Naumann, U., Kelley, N., Oakeley, E. J., Mueller, M., Gomez Mancilla, B., Bühler, M., Tabolacci, E., Chiurazzi, P., Neri, G., Bouwmeester, T., Di Giorgio, F. P., Fodor, B. D., CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations, <<STEM CELL REPORTS>>, 2016; 7 (6): 1059-1071. [doi:10.1016/j.stemcr.2016.10.004] [http://hdl.handle.net/10807/93630]

CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations

Tabolacci, Elisabetta;Chiurazzi, Pietro;Neri, Giovanni;
2016

Abstract

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.
2016
Inglese
Brykczynska, U., Pecho Vrieseling, E., Thiemeyer, A., Klein, J., Fruh, I., Doll, T., Manneville, C., Fuchs, S., Iazeolla, M., Beibel, M., Roma, G., Naumann, U., Kelley, N., Oakeley, E. J., Mueller, M., Gomez Mancilla, B., Bühler, M., Tabolacci, E., Chiurazzi, P., Neri, G., Bouwmeester, T., Di Giorgio, F. P., Fodor, B. D., CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations, <<STEM CELL REPORTS>>, 2016; 7 (6): 1059-1071. [doi:10.1016/j.stemcr.2016.10.004] [http://hdl.handle.net/10807/93630]
File in questo prodotto:
File Dimensione Formato  
Stem Cell Reports.pdf

accesso aperto

Tipologia file ?: Versione Editoriale (PDF)
Licenza: Creative commons
Dimensione 2.02 MB
Formato Adobe PDF
2.02 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/93630
Citazioni
  • ???jsp.display-item.citation.pmc??? 14
  • Scopus 22
  • ???jsp.display-item.citation.isi??? 18
social impact