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

Elisabetta Tabolacci, Pietro Chiurazzi, Giovanni Neri, Urszula Brykczynska, Eline Pecho-Vrieseling, Anke Thiemeyer, Jessica Klein, Isabelle Fruh, Thierry Doll, Carole Manneville, Sascha Fuchs, Mariavittoria Iazeolla, Martin Beibel, Guglielmo Roma, Ulrike Naumann, Nicholas Kelley, Edward J. Oakeley, Matthias Mueller, Baltazar Gomez-Mancilla, Marc BühlerTewis Bouwmeester, Francesco Paolo Di Giorgio, Barna D. Fodor

Risultato della ricerca: Contributo in rivistaArticolo in rivista

13 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)1059-1071
Numero di pagine13
RivistaStem Cell Reports
Volume7
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • Biochemistry
  • CGG repeat
  • Cell Biology
  • DNA methylation
  • Developmental Biology
  • FMR1
  • Genetics
  • de novo silencing
  • fragile X syndrome
  • fragile X tremor ataxia syndrome
  • neuron
  • triplet expansion
  • ubiquitin inclusion
  • unmethylated full mutation

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