Role of repeat-associated microRNA (ramRNA) in fragile X syndrome (FXS)

Abstract

A large portion of the genome is non-coding DNA, which frequently contains redundant microsatellite-like trinucleotide repeats with function not yet to be known. Recent studies have shown that many of these trinucleotide repeats are involved in triplet repeat expansion diseases (TREDs), such as fragile X syndrome (FXS), Huntington's disease (HD), myotonic dystrophy (DM), and a number of spinocerebellar ataxias (SCAs). The trinucleotide repeats can fold into RNA hairpins and are further processed by Dicer to form microRNA (miRNA)-like molecules, capable of triggering targeted gene-silencing effects in the TREDs; however, the pathogenic mechanism of these repeat-associated miRNAs (ramRNAs) is unclear. To resolve this question, we have identified the first native ramRNAs in FXS and successfully developed a ramRNA-mediated transgenic zebrafish model for studying the role of the ramRNAs in FXS-related neurodegeneration. Based on this model, we found that ramRNA-induced DNA methylation of the FMR1 5′-UTR CGG trinucleotide repeat expansion is central to FXS etiology. This epigenetic modification leads to physical, neurocognitive and emotional characteristics linked to the transcriptional FMR1 gene inactivation and the deficiency of its protein product. FMR1 deficiency often causes synapse deformity in the neurons essential for cognition and memory activities. Furthermore, the metabotropic glutamate receptor (mGluR)-activated long-term depression (LTD) is augmented after the FMR1 inactivation, suggesting that exaggerated LTD may be responsible for aspects of abnormal neuronal responses in FXS, such as autism. Therefore, the establishment of this ramRNA-mediated transgenic animal model provides a new avenue to dissect the physiopathological and epigenetic alterations of TREDs affected by the microsatellite-like trinucleotide repeat expansions, with the hope of providing insights into areas of opportunity for therapeutic intervention.