2 research outputs found
Changes in expression of the long non-coding RNA FMR4 associate with altered gene expression during differentiation of human neural precursor cells
CGG repeat expansions in the Fragile X mental retardation 1 (
FMR1
) gene are responsible for a family of associated disorders characterized by either intellectual disability and autism Fragile X Syndrome (FXS), or adult-onset neurodegeneration Fragile X-associated Tremor/Ataxia Syndrome. However, the
FMR1
locus is complex and encodes several long non-coding RNAs, whose expression is altered by repeat expansion mutations. The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of
FMR4
, which we previously identified. “Full”-length expansions of the
FMR1
triplet repeat cause silencing of both
FMR1
and
FMR4
, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. Since the two transcripts do not exhibit
cis
-regulation of one another, we examined the potential for
FMR4
to regulate target genes at distal genomic loci using gene expression microarrays. We identified
FMR4
-responsive genes, including the methyl-CpG-binding domain protein 4 (
MBD4
). Furthermore, we found that in differentiating human neural precursor cells,
FMR4
expression is developmentally regulated in opposition to expression of both
FMR1
(which is expected to share a bidirectional promoter with
FMR4
) and
MBD4
. We therefore propose that
FMR4
’s function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of
FMR4
increases our understanding of the role of regulatory lncRNA and the consequences of
FMR1
repeat expansions
The long non-coding RNA FMR4 promotes proliferation of human neural precursor cells and epigenetic regulation of gene expression in trans
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