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Science. 2014 Feb 28;343(6174):1002-5. doi: 10.1126/science.1245831.

Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome.

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  • 1Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.

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┬ĚDNA 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.

PMID:
24578575
[PubMed - indexed for MEDLINE]
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