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

Dilek Colak, Nikica Zaninovic, Michael Cohen, Zev Rosenwaks, Wang Yong Yang, Jeannine Gerhardt, Matthew D. Disney, Samie R. Jaffrey

Research output: Contribution to journalArticle

144 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1002-1005
Number of pages4
JournalScience
Volume343
Issue number6174
DOIs
StatePublished - 2014

Fingerprint

Trinucleotide Repeats
Fragile X Syndrome
Epigenomics
Intellectual Disability
Messenger RNA
Trinucleotide Repeat Expansion
Gene Silencing
RNA
Genes
5' Untranslated Regions
Drive
Repeats
Mental Retardation
Epigenetics
Syndrome
Gene
DNA

ASJC Scopus subject areas

  • General
  • History and Philosophy of Science
  • Medicine(all)

Cite this

Colak, D., Zaninovic, N., Cohen, M., Rosenwaks, Z., Yang, W. Y., Gerhardt, J., ... Jaffrey, S. R. (2014). Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. Science, 343(6174), 1002-1005. https://doi.org/10.1126/science.1245831

Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. / Colak, Dilek; Zaninovic, Nikica; Cohen, Michael; Rosenwaks, Zev; Yang, Wang Yong; Gerhardt, Jeannine; Disney, Matthew D.; Jaffrey, Samie R.

In: Science, Vol. 343, No. 6174, 2014, p. 1002-1005.

Research output: Contribution to journalArticle

Colak, D, Zaninovic, N, Cohen, M, Rosenwaks, Z, Yang, WY, Gerhardt, J, Disney, MD & Jaffrey, SR 2014, 'Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome', Science, vol. 343, no. 6174, pp. 1002-1005. https://doi.org/10.1126/science.1245831
Colak, Dilek ; Zaninovic, Nikica ; Cohen, Michael ; Rosenwaks, Zev ; Yang, Wang Yong ; Gerhardt, Jeannine ; Disney, Matthew D. ; Jaffrey, Samie R. / Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. In: Science. 2014 ; Vol. 343, No. 6174. pp. 1002-1005.
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