Int. J. Dev. Biol. 61: 285 - 292 (2017)
doi: 10.1387/ijdb.170022hc
© UPV/EHU Press

Epigenetic mechanism of FMR1 inactivation in Fragile X syndrome

Merav Hecht1, Amalia Tabib1, Tamar Kahan1, Shari Orlanski1, Michal Gropp3, Yuval Tabach1, Ofra Yanuka2, Nissim Benvenisty2, Ilana Keshet1 and Howard Cedar*,1

1Department of Developmental Biology and Cancer Research, 2Department of Genetics, Hebrew University, Jerusalem and 3 The Sydney and Judy Swartz Human Embryonic Stem Cell Research Center, Hadassah-Hebrew University Medical Center Jerusalem, Israel

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.

Keywords:

DNA methylation, chromatin, RNAi, histone modification

*Corresponding author e-mail: cedar@mail.huji.ac.il