Int. J. Dev. Biol. 61: 285 - 292 (2017)

https://doi.org/10.1387/ijdb.170022hc

Vol 61, Issue 3-4-5

Special Issue: Developmental Biology in Israel

Epigenetic mechanism of FMR1 inactivation in Fragile X syndrome

Published: 2 June 2017

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