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Genome-wide screening for genes involved in the epigenetic basis of fragile X syndrome

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  • Dan Vershkov, Hebrew University of Jerusalem
  • ,
  • Atilgan Yilmaz, Hebrew University of Jerusalem
  • ,
  • Ofra Yanuka, Hebrew University of Jerusalem
  • ,
  • Anders Lade Nielsen
  • Nissim Benvenisty, Hebrew University of Jerusalem

Fragile X syndrome (FXS), the most prevalent heritable form of intellectual disability, is caused by the transcriptional silencing of the FMR1 gene. The epigenetic factors responsible for FMR1 inactivation are largely unknown. Here, we initially demonstrated the feasibility of FMR1 reactivation by targeting a single epigenetic factor, DNMT1. Next, we established a model system for FMR1 silencing using a construct containing the FXS-related mutation upstream to a reporter gene. This construct was methylated in vitro and introduced into a genome-wide loss-of-function (LOF) library established in haploid human pluripotent stem cells (PSCs), allowing the identification of genes whose functional loss reversed the methylation-induced silencing of the FMR1 reporter. Selected candidate genes were further analyzed in haploid- and FXS-patient-derived PSCs, highlighting the epigenetic and metabolic pathways involved in FMR1 regulation. Our work sheds light on the mechanisms responsible for CGG-expansion-mediated FMR1 inactivation and offers novel targets for therapeutic FMR1 reactivation.

Original languageEnglish
JournalStem Cell Reports
Pages (from-to)1048-1058
Number of pages11
Publication statusPublished - May 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

    Research areas

  • fragile X syndrome, genetic screening, human pluripotent stem cells

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