CGG repeat-induced FMR1 silencing depends on the expansion size in human iPSCs and neurons carrying unmethylated full mutations.

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

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. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Journal: Stem cell reports
DOI: 10.1016/j.stemcr.2016.10.004
Year: 2016

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