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.

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

“…In the context of FXS research, the use of FX-hESCs as opposed to FX-hiPSCs can greatly affect the results obtained. The current literature clearly indicates that reprogramming of fibroblasts from FXS patients does not erase the methylation pattern of an expanded FMR1 allele, while FX-hESCs have mostly unmethylated FMR1 loci [16,17,[61][62][63][64][65][66]. In accordance, the results obtained from these two models can vary significantly.…”

Fragile X full mutation expansions are inhibited by one or more AGG interruptions in premutation carriers

“…[2][3][4] Full mutation alleles are silenced by a process analogous to X inactivation, which results in the absence of the gene product, FMRP, and the FXS in males and some females. 5 Although the repeat is highly stable when transmitted from individuals with normal alleles , it is remarkably unstable on maternal transmission of premutation alleles (55-200 CGGs), which frequently expand to the full mutation in one generation. This risk of full mutation expansion increases with maternal CGG repeat length to nearly 100% for mothers with >90 CGGs.…”

Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome

“…Affected individuals exhibit mental retardation, attention deficit and hyperactivity, anxiety, autism spectrum behaviors, and other symptoms that compound overall impairment (1). In the vast majority of cases, FXS is caused by an mRNA-dependent epigenetic silencing of the Fmr1 (fragile X mental retardation 1) gene (2), which occurs secondarily to a CGG repeat expansion in the 5′ UTR region of Fmr1 (3) and results in absence of the encoded protein FMRP. FMRP is an RNA-binding protein that regulates several aspects of mRNA translation (1), transport (4), and stability (5) in neurons.…”