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Promoter-Bound Trinucleotide Repeat mRNA Drives Epigenetic Silencing in Fragile X Syndrome

Science  28 Feb 2014:
Vol. 343, Issue 6174, pp. 1002-1005
DOI: 10.1126/science.1245831

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Repeat Silencing

Fragile X syndrome, a genetic cause of many cases of autism and mental retardation, involves expansion of a trinucleotide repeat in the fragile X mental retardation 1 (FMR1) gene. Working with human embryonic stem cells, Colak et al. (p. 1002) found that the expanded repeat region was transcribed into the untranslated region of FMR1 messenger RNA, which then bound to the DNA repeat region in the FMR1 gene, inactivating the gene. The findings explain how the trinucleotide repeat expansion causes RNA-directed gene silencing during development in fragile X syndrome.

Abstract

Epigenetic gene silencing is seen in several repeat-expansion diseases. In fragile X syndrome, the most common genetic form of mental retardation, a CGG trinucleotide–repeat expansion adjacent to the fragile X mental retardation 1 (FMR1) gene promoter results in its epigenetic silencing. Here, we show that FMR1 silencing is mediated by the FMR1 mRNA. The FMR1 mRNA contains the transcribed CGG-repeat tract as part of the 5′ untranslated region, which hybridizes to the complementary CGG-repeat portion of the FMR1 gene to form an RNA·DNA duplex. Disrupting the interaction of the mRNA with the CGG-repeat portion of the FMR1 gene prevents promoter silencing. Thus, our data link trinucleotide-repeat expansion to a form of RNA-directed gene silencing mediated by direct interactions of the trinucleotide-repeat RNA and DNA.

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