The long non-coding RNA FMR4 promotes proliferation of human neural precursor cells and epigenetic regulation of gene expression in trans

Abstract

Triplet repeat expansions in the Fragile X mental retardation 1 (FMR1) gene cause either intellectual disability and autism, or adult-onset neurodegeneration, with poorly understood variability in presentation. Previous studies have identified several long noncoding RNAs (lncRNAs) at the FMR1 locus, including FMR4. Similarly to FMR1, FMR4 is silenced by large-repeat expansions that result in enrichment of DNA and histone methylation within the shared promoter and repeat sequence, suggesting a possible role for this noncoding RNA in the pathophysiology of Fragile X. We therefore assessed the functional role of FMR4 to gain further insight into the molecular processes in Fragile X-associated disorders. Previous work showed that FMR4 does not exhibit cis-regulation of FMR1. Here, we found that FMR4 is a chromatin-associated transcript and, using genome-wide chromatin immunoprecipitation experiments, showed that FMR4 alters the chromatin state and the expression of several hundred genes in trans. Among the genes regulated by FMR4, we found enrichment for those involved in neural development and cellular proliferation. S-phase marker assays further demonstrated that FMR4 may promote cellular proliferation, rather than differentiation, of human neural precursor cells (hNPCs). By establishing this novel function for FMR4 in hNPCs, we lend support to existing evidence of the epigenetic involvement of lncRNA in nervous system development, and increase our understanding of the complex pathogenesis underlying neurological disorders associated with FMR1 repeat expansions.

Acute Ethanol Produces Ataxia and Induces Fmr1 Expression via Histone Modifications in the Rat Cerebellum

“…They also expand upon limited recent research illustrating a role for Fmr1 following EtOH exposure, albeit one that was, until now, exclusive to the hippocampus (Mulholland et al., ; Spencer et al., ; Wolfe et al., ). Fmr1 is a dynamic epigenetic target that can alter expression of hundreds of transcripts, but that itself may also be regulated by microRNAs (Kenny et al., ; Liu et al., ; Tan et al., ) or its own noncoding antisense RNA Fxr4 (Pastori et al., ; Peschansky et al., ). Given that acute and chronic EtOH alter microRNA and long noncoding RNA networks (Miranda et al., ; Osterndorff‐Kahanek et al., ; Teppen et al., ), future experiments should examine other epigenetic regulations of Fmr1 beyond the histone acetylation examined here in order to further elucidate the role of Fmr1 and its regulatory gene network in the neural response to EtOH, particularly the ataxic effects of EtOH.…”

LncRNA mediated regulation of aging pathways in Drosophila melanogaster during dietary restriction

“…LncRNAs have regulatory roles in gene expression at both the transcriptional and post-transcriptional levels in diverse cellular contexts and biological processes. lncRNAs are responsible for nuclear structure integrity, and can regulate the expression of either nearby genes (acting in cis in the nucleus) or genes elsewhere in cells (acting in trans in the nucleus or cytoplasm) by interacting with proteins, RNAs, and DNAs [ 55 , 56 ]. Cis acting lncRNAs are those acting on neighboring target genes [ 55 ].…”

The Long Non-Coding RNAs in Neurodegenerative Diseases: Novel Mechanisms of Pathogenesis

“…Among these genes, there was an enrichment for those involved in neural development and cellular proliferation. Indeed, it was further demonstrated that FMR1-AS1 may promote cellular proliferation of hNPCs [91]. It was also proposed that altered FMR1-AS1 expression might contribute to some clinical aspects of FXS/FXTAS [89].…”