Epigenetic mechanism of FMR1 inactivation in Fragile X syndrome

Merav Hecht, Amalia Tabib, Tamar Kahan, Shari Orlanski, Michal Gropp, Yuval Tabach, Ofra Yanuka, Nissim Benvenisty, Ilana Keshet, Howard Cedar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Fragile X syndrome is the most frequent cause of inherited intellectual disability. The primary molecular defect in this disease is the expansion of a CGG repeat in the 5’ region of the fragile X mental retardation1 (FMR1) gene, leading to de novo methylation of the promoter and inactivation of this otherwise normal gene, but little is known about how these epigenetic changes occur during development. In order to gain insight into the nature of this process, we have used cell fusion technology to recapitulate the events that occur during early embryogenesis. These experiments suggest that the naturally occurring Fragile XFMR1 5′ region undergoes inactivation post implantation in a Dicer/Ago-dependent targeted process which involves local SUV39H-mediated tri-methylation of histone H3K9. It thus appears that Fragile X syndrome may come about through inadvertent siRNA-mediated heterochromatinization.

Original languageAmerican English
Pages (from-to)285-292
Number of pages8
JournalInternational Journal of Developmental Biology
Volume61
Issue number3-5
DOIs
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© 2017 UPV/EHU Press.

Keywords

  • Chromatin
  • DNA methylation
  • Histone modification
  • RNAi

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