Abstract
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.
