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Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing 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.

SUBMITTER: Colak D

PROVIDER: S-EPMC4357282 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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

Colak Dilek D Zaninovic Nikica N Cohen Michael S MS Rosenwaks Zev Z Yang Wang-Yong WY Gerhardt Jeannine J Disney Matthew D MD Jaffrey Samie R SR

Science (New York, N.Y.) 20140201 6174

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 por ...[more]

PMID: 24578575

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