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

Dan Vershkov, Atilgan Yilmaz, Ofra Yanuka, Anders Lade Nielsen, Nissim Benvenisty

Research output: Contribution to journalArticlepeer-review


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 languageAmerican English
Pages (from-to)1048-1058
Number of pages11
JournalStem Cell Reports
Issue number5
StatePublished - 10 May 2022


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

All Science Journal Classification (ASJC) codes

  • Genetics
  • Biochemistry
  • Cell Biology
  • Developmental Biology


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