title: 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.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Dilek
authors.initials: D
authors.lastname: Colak
authors.forename: Nikica
authors.initials: N
authors.lastname: Zaninovic
authors.forename: Michael S
authors.initials: MS
authors.lastname: Cohen
authors.forename: Zev
authors.initials: Z
authors.lastname: Rosenwaks
authors.forename: Wang-Yong
authors.initials: WY
authors.lastname: Yang
authors.forename: Jeannine
authors.initials: J
authors.lastname: Gerhardt
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Disney
authors.forename: Samie R
authors.initials: SR
authors.lastname: Jaffrey
mesh_terms: D000818:Animals; D002460:Cell Line; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C099930:AFF2 protein, human; C497683:FMR1 protein, human