Epigenetic mechanism of FMR1 inactivation in Fragile X syndrome

• Published in: The International journal of developmental biology Vol. 61; no. 3-4-5; pp. 285 - 292
• Main Authors: Hecht, Merav, Tabib, Amalia, Kahan, Tamar, Orlanski, Shari, Gropp, Michal, Tabach, Yuval, Yanuka, Ofra, Benvenisty, Nissim, Keshet, Ilana, Cedar, Howard
• Format: Journal Article
• Language: English
• Published: Spain 2017
• Subjects: 5' Untranslated Regions; Animals; Cell Differentiation; DNA Methylation; Embryonic Development; Embryonic Stem Cells - metabolism; Epigenesis, Genetic; Fibroblasts - metabolism; Fragile X Mental Retardation Protein - genetics; Fragile X Syndrome - genetics; Gene Expression Regulation, Developmental; Heterochromatin - chemistry; Histones - metabolism; Humans; Mice; Nerve Tissue Proteins - genetics; Phenotype; Promoter Regions, Genetic; RNA - metabolism; RNA Interference; RNA, Small Interfering - metabolism
• ISSN: 0214-6282; 1696-3547
• DOI: 10.1387/ijdb.170022hc

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.