FMR1 Epigenetic Silencing Commonly Occurs in Undifferentiated Fragile X-Affected Embryonic Stem Cells

Avitzour, Michal; Mor‐Shaked, Hagar; Yanovsky‐Dagan, Shira; Aharoni, Shira; Altarescu, Gheona; Renbaum, Paul; Eldar‐Geva, Talia; Schonberger, Oshrat; Levy-Lahad, Ephrat; Epsztejn‐Litman, Silvina; Eiges, Rachel

doi:10.1016/j.stemcr.2014.09.001

Cited by 67 publications

(92 citation statements)

References 28 publications

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“…In the context of FXS research, the use of FX-hESCs as opposed to FX-hiPSCs can greatly affect the results obtained. The current literature clearly indicates that reprogramming of fibroblasts from FXS patients does not erase the methylation pattern of an expanded FMR1 allele, while FX-hESCs have mostly unmethylated FMR1 loci [16,17,[61][62][63][64][65][66]. In accordance, the results obtained from these two models can vary significantly.…”

Section: Discussionmentioning

confidence: 68%

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

Telias

Mayshar

Amit

et al. 2015

Stem Cells and Development

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Fragile X syndrome (FXS) is the most common form of inherited cognitive impairment. It is caused by developmental inactivation of the FMR1 gene and the absence of its encoded protein FMRP, which plays pivotal roles in brain development and function. In FXS embryos with full FMR1 mutation, FMRP is expressed during early embryogenesis and is gradually downregulated at the third trimester of pregnancy. FX-human embryonic stem cells (FX-hESCs), derived from FX human blastocysts, demonstrate the same pattern of developmentally regulated FMR1 inactivation when subjected to in vitro neural differentiation (IVND). In this study, we used this in vitro human platform to explore the molecular mechanisms downstream to FMRP in the context of early human embryonic neurogenesis. Our results show a novel role for the SOX superfamily of transcription factors, specifically for SOX2 and SOX9, which could explain the reduced and delayed neurogenesis observed in FX cells. In addition, we assess in this study the ''GSK3b theory of FXS'' for the first time in a human-based model. We found no evidence for a pathological increase in GSK3b protein levels upon cellular loss of FMRP, in contrast to what was found in the brain of Fmr1 knockout mice. Our study adds novel data on potential downstream targets of FMRP and highlights the importance of the FX-hESC IVND system.

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Section: Discussionmentioning

confidence: 68%

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

Telias

Mayshar

Amit

et al. 2015

Stem Cells and Development

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“…With this CGG repeat level, the FMR1 gene is typically hypermethylated leading to transcriptional silencing and low or absent FMR protein levels [70]. At the embryonic stem cell level, the hypermethylation-coupled epigenetic silencing and subsequent lack of the FMR1 protein does affect the development and function of synapses [3] This sequence of events leads to the fragile X syndrome (FXS), where intellectual disabilities and an autism spectrum disorder manifests predominantly in males. In FXS, the alleles are highly unstable, through maternal transmission, and CGG repeat expansion often rises in the subsequent generations [98] (Fig.…”

Section: The Cgg Mutationsmentioning

confidence: 99%

“…Additionally, through the influence of AMPA receptor trafficking anomalies, the synapses weaken [2,67]. Avitzour hypothesized that this gene silencing most probably occurs at the embryonic stem cell level [3]. (see Table 1).…”

Section: How Fmr1 Mutations Influence Different Phenotypesmentioning

confidence: 99%

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Noto

Harrity

Walsh

et al. 2016

J Assist Reprod Genet

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Purpose This is a comprehensive review of the literature in this field attempting to put the FMR1 gene and its evaluation into context, both in general and for the reproductive health audience. Methods Online database search of publications with systematic review of all papers relevant to ovarian reserve and assisted reproduction was done. Results Relevant papers were identified and assessed, and an attempt was made to understand, rationalize and explain the divergent views in this field of study. Seminal and original illustrations were employed. Conclusions FMR1 is a highly conserved gene whose interpretation and effect on outcomes remains controversial in the reproductive health setting. Recent re-evaluations of the commonly accepted normal range have yielded interesting tools for possibly explaining unexpected outcomes in assisted reproduction. Fragile X investigations should perhaps become more routinely assessed in the reproductive health setting, particularly following a failed treatment cycle where oocyte quality is thought to be a contributing factor, or in the presence of a surprise finding of diminished ovarian reserve in a young patient.

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“…Importantly, inactivation of FMR1 is developmentally regulated and, in FXS human embryos, FMR1 silencing is observed only by the end of the first trimester of pregnancy (Willemsen et al, 2002). This feature of FXS pathology is recapitulated during differentiation of FX human embryonic stem cells (FX-hESCs) (Eiges et al, 2007;Telias et al, 2013;Avitzour et al, 2014;Colak et al, 2014), but not in FMR1 knock-out animal models (Moy and Nadler;Santos et al, 2014) or in FX human induced pluripotent stem cells (FX-hiPSCs) (Urbach et al, 2010, Sheridan et al, 2011Doers et al, 2014). Human-based FXS in vitro models have been established using neural progenitor cells established from aborted fetuses (Castren et al, 2005;.…”

Section: Introductionmentioning

confidence: 99%

Functional Deficiencies in Fragile X Neurons Derived from Human Embryonic Stem Cells

et al. 2015

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Fragile X syndrome (FXS), the most common form of inherited mental retardation, is a neurodevelopmental disorder caused by silencing of the FMR1 gene, which in FXS becomes inactivated during human embryonic development. We have shown recently that this process is recapitulated by in vitro neural differentiation of FX human embryonic stem cells (FX-hESCs), derived from FXS blastocysts. In the present study, we analyzed morphological and functional properties of neurons generated from FX-hESCs. Human FX neurons can fire single action potentials (APs) to depolarizing current commands, but are unable to discharge trains of APs. Their APs are of a reduced amplitudes and longer durations than controls. These are reflected in reduced inward Na ϩ and outward K ϩ currents. In addition, human FX neurons contain fewer synaptic vesicles and lack spontaneous synaptic activity. Notably, synaptic activity in these neurons can be restored by coculturing them with normal rat hippocampal neurons, demonstrating a critical role for synaptic mechanisms in FXS pathology. This is the first extensive functional analysis of human FX neurons derived in vitro from hESCs that provides a convenient tool for studying molecular mechanisms underlying the impaired neuronal functions in FXS.

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FMR1 Epigenetic Silencing Commonly Occurs in Undifferentiated Fragile X-Affected Embryonic Stem Cells

Cited by 67 publications

References 28 publications

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Functional Deficiencies in Fragile X Neurons Derived from Human Embryonic Stem Cells

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