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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.

OriginalsprogEngelsk
TidsskriftStem Cell Reports
Vol/bind17
Nummer5
Sider (fra-til)1048-1058
Antal sider11
ISSN2213-6711
DOI
StatusUdgivet - maj 2022

Bibliografisk note

Funding Information:
The authors would like to thank Tamar Golan-Lev and Aviva Petcho for their help with tissue cultures and Elyad Lezmi for critically reading the manuscript. The study was partially supported by the Azrieli Foundation by the Rosetrees Trust and by the ISF-Israel Precision Medicine Partnership (IPMP) Program (no. 3605/21). N.B. is the Herbert Cohn Chair in Cancer Research.

Funding Information:
The authors would like to thank Tamar Golan-Lev and Aviva Petcho for their help with tissue cultures and Elyad Lezmi for critically reading the manuscript. The study was partially supported by the Azrieli Foundation by the Rosetrees Trust and by the ISF -Israel Precision Medicine Partnership (IPMP) Program (no. 3605/21 ). N.B. is the Herbert Cohn Chair in Cancer Research.

Publisher Copyright:
© 2022 The Author(s)

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