TY - JOUR
T1 - CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations
AU - Brykczynska, Urszula
AU - Pecho Vrieseling, Eline
AU - Thiemeyer, Anke
AU - Klein, Jessica
AU - Fruh, Isabelle
AU - Doll, Thierry
AU - Manneville, Carole
AU - Fuchs, Sascha
AU - Iazeolla, Mariavittoria
AU - Beibel, Martin
AU - Roma, Guglielmo
AU - Naumann, Ulrike
AU - Kelley, Nicholas
AU - Oakeley, Edward J.
AU - Mueller, Matthias
AU - Gomez Mancilla, Baltazar
AU - Bühler, Marc
AU - Tabolacci, Elisabetta
AU - Chiurazzi, Pietro
AU - Neri, Giovanni
AU - Bouwmeester, Tewis
AU - Di Giorgio, Francesco Paolo
AU - Fodor, Barna D.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Biochemistry
KW - CGG repeat
KW - Cell Biology
KW - DNA methylation
KW - Developmental Biology
KW - FMR1
KW - Genetics
KW - de novo silencing
KW - fragile X syndrome
KW - fragile X tremor ataxia syndrome
KW - neuron
KW - triplet expansion
KW - ubiquitin inclusion
KW - unmethylated full mutation
KW - Biochemistry
KW - CGG repeat
KW - Cell Biology
KW - DNA methylation
KW - Developmental Biology
KW - FMR1
KW - Genetics
KW - de novo silencing
KW - fragile X syndrome
KW - fragile X tremor ataxia syndrome
KW - neuron
KW - triplet expansion
KW - ubiquitin inclusion
KW - unmethylated full mutation
UR - https://publicatt.unicatt.it/handle/10807/93630
UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=85004028163&origin=inward
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85004028163&origin=inward
U2 - 10.1016/j.stemcr.2016.10.004
DO - 10.1016/j.stemcr.2016.10.004
M3 - Article
SN - 2213-6711
VL - 7
SP - 1059
EP - 1071
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 6
ER -