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Computational Molecular Biology 2014, Vol. 4, No. 5
http://cmb.biopublisher.ca
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enhancer. The enhancer lncRNAs were also found in
the intergenic region that are between the Dlx-5 and
Dlx-6 loci within the Dlx loci. The region covers with
a piece of conserved intergenic enhancer (Zerucha et
al., 2000). Dlx-6 is a homeobox element and itself a
transcription factor and is vital in embryonic brain
developmnet (Wang et al., 2010).
1.3 Regulation of lncRNA expression in the nervous
system
How lncRNAs are regulated in CNS and what factors
can influence lncRNA expression are not well
understood. The main ideas are that lncRNAs are
under similar regulatory mechanisms with that of
protein-coding genes (Dinger et al., 2008; Guttman et
al., 2009; Cawley et al., 2004; Mercer et al., 2010;
Zhang et al., 2009). For instance, Pax2, a transcription
factor, functions in formation of the mouse brain;
while Ncrms is a lncRNA that is exactly mediated via
Pax2 (Bouchard et al., 2005). Interestingly, Ncrms is
the host gene for miR-135a (Rodriguez et al., 2004), a
miRNA, which has reversed expression pattern in
medulloblastoma, compared with normal brain
(Ferretti et al., 2009). The evidences suggest that
genetic and epigenetic factors can both mediate
tumorigenesis. In another example, Sox2, which is a
pluripotency related transcription factor, plays an
important role in the preservation of the Neural Stem
Cells (NSCs) in embryonic and adult brain (Pevny and
Placzek, 2005). In Sox2 gene loci, a lncRNA exists,
which is named by Sox2 overlapping transcript
(Sox2OT). Genomic studies showed that it shares
same transcriptional direction with the Sox2 gene.
Sox2 and Sox2OT transcribe stably in mouse
embryonic stem cells and are down regulated during
stem cell differentiation. Amaral et al. detected that in
the neurogenic region of the adult mouse brain
Sox2OT is expressed and is under dynamic regulation
during CNS development, suggesting that it can
regulate the self-renewal and neurogenesis of stem
cells (Amaral et al., 2009).
Nkx2.2as, which is a lncRNA antisense to the Nkx2.2
gene, is transcribed in the embryonic brain and is
necessary to oligodendrocyte development (Price et al.,
1992). Aberrant transcription of Nkx2.2as in Neural
Stem Cell (NSC) can induce the oligodendrocyte
differentiation by Nkx2.2 upregulation, indicating that
Nkx2.2as regulates NSC differentiation by increasing
the expression of Nkx2.2 (Tochitani and Hayashizaki,
2008).
In addition, recent evidences imply that the perturbed
epigenetic processes can alter the lncRNA expression
patterns (Mattick, 2009). When treated with
trichostatin A (TSA), OL development process is
changed. OL maturation is inhibited by TSA which is
a histone deacetylase inhibitor by suppressing
OL-specific gene expression (Mercer et al., 2010). We
summarized the examples of loss of gene function
studies in brain and CNS in Table 1, which can be
achieved by locally administered RNA interference
(RNAi) reagents. Taken together, it is indicated that
lncRNAs are regulated by similar transcriptional and
epigenetic factors with protein-coding genes.
Though lncRNAs are expressed across various tissues,
the functions in brain development can be explored if
using a traditional knockout approach. For instance,
mice with knockouts of lncRNAs Hotair (Li et al.,
2013) and Xist (Marahrens et al., 1997) resulted in
severe phenotypes, but mice with a knockout of the
ubiquitously and highly expressed lncRNA Malat1
displayed no obvious phenotype (Eissmann et al.,
2012). Regulation of synaptogenesis (Bernard et al.,
2010), alternative splicing (Tripathi et al., 2010),
control of cell cycles (Tripathi et al., 2013) and
diseases (Gutschner et al., 2013) have been reported
for Malat1, but it is still unknown what the precise
role is for this abundant and broadly expressed
lncRNA. The results indicated that further functional
analyses are needed, which is helpful to uncover the
functional roles within neural cells.
2 lncRNAs in diseases of the CNS and brain
Disruptions to genome-wide lncRNA-mediated
functions could have negative consequences, which is
particularly important in the mammalian brain and
nervous system where most tissue-specific lncRNAs
are expressed. Indeed, it is emerging that lncRNAs are
involved in the pathology of neurological diseases
related to imprinting, for instance, Prader–Willi
syndrome (PWS) and Angelman syndrome (AS)
(Koerner et al., 2009). Additionally, lncRNAs that are