and plays a critical role in the p53 transcriptional response by targeting chromatin-modifying complexes to specific genomic loci.78 While p53 is known to transcriptionally activate numer- ous genes, the mechanisms by which p53 leads to gene repression have remained elusive. Huarte et al. propose an elegant mecha- nism by which p53 globally downregulates a large subset of its targets. This study emphasizes the significance of lincRNA acti- vation in the control of transcriptional programs that maintain cellular homeostasis. Since these lincRNAs are part of p53-medi- ated genome surveillance, it can be argued that tumors lacking functional p53, e.g., glioblastomas, might display altered expres- sion of lincRNAs. Another recent study identified PANDA, a lincRNA that is 5 kb upstream of CDKN1A (p21). PANDA is induced by p53 and interacts with the transcription factor NF-YA to limit the expression of pro-apoptotic genes.79 Thus, the regu- latory sequence upstream of CDKN1A drives the expression of multiple noncoding transcripts that coordinate the DNA damage response in healthy cells. Inactivation, overexpression and copy number variations in the transcriptional repressor REST have been reported in sev- eral cancers. REST is a master negative regulator of neurogenesis that represses neuronal genes in non-neuronal tissues. Altered expression of REST may promote the loss of cellular identity and induce transformation through alterations in genomic stabil- ity, DNA methylation, chromatin remodeling and deregulation of onco- and tumor suppressor genes.80 Abrajano et al. demon- strated that in glial cells both REST and CoREST modulate genes in key neuronal pathways.80 This suggests that CoREST, like REST, might play a role in cellular transformation in the nervous system. Interestingly, the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes: PRC1 (LSD1/CoREST/REST) and PRC2.81 HOTAIR interac- tion with these distinct complexes leads to the coordinated tar- geting of both to chromatin. Hence, we can speculate that the deregulation of REST in brain cancers might result in epigenetic alterations depending on the delocalization of this and poten- tially many other lncRNAs to their target loci. A better charac- terization of how REST and CoREST coordinate the epigenetic programming of neural cells can help us to better understand neural development and cancer.82-84 The polycomb repressive complex (PRC2) catalyzes the tri- methylation of histone 3 on lysine 27 (H3K27me3), to silence chromatin, altering the degree of chromatin compaction and consequently the rate of gene transcription. The mechanism by which mammalian PRC2 is recruited to chromatin is unclear. In mammals, PRC2-targeted sequences consist mostly of CpG islands, but these sequences alone do not indicate a consensus response element.85 Long ncRNAs are becoming recognized as important mediators of PRC2 genomic recruitment19,20,23,81,86,87 and such an interaction could be common to a large number of long ncRNAs. Ezh2, the catalytic subunit of the PRC2 complex has been reported to interact with lncRNAs Xist,86 HOTAIR,88 ANRIL87 and numerous lincRNAs.22 Mutations in Ezh2 have been observed in lymphoma89 and its overexpression is an indicator of advanced and metastatic disease in many solid tumors90 as well as gliomas, according to a recent report.91 Thus, deregulation of both chromatin modifier enzymes and the lncRNAs that associ- ate to them could easily lead to disruptions in chromatin regula- tion, potentially resulting in oncogenesis. Imprinted LncRNAs and CNS tumors. It has long been sug- gested that chromosome 14q32 contains genes involved in the pathogenesis and progression of meningioma, a CNS tumor arising from arachnoid cells that line the brain and spinal cord. Maternally expressed gene 3 (MEG3), is an imprinted gene located on chromosome 14q32 that produces a highly expressed non- coding RNA in normal human brains that is lost in high grade meningiomas.92 Interestingly, the expression of MEG3 in human meningioma cell lines strongly suppresses tumor cell growth and activates p53-mediated apoptosis,92 suggesting a tumor-suppres- sive activity for this noncoding RNA. H19 is another example of an imprinted long noncoding RNA associated with CNS cancer. H19 is expressed during embryogenesis and the deregulation of H19 and other imprinted genes in this cluster are reported to promote cell transformation in a number of tumors, including gliomas. H19 is a target of the GLI1 transcription factor that mediates the Sonic Hedgehog signaling pathway and is ampli- fied more than 50-fold in human gliomas.93 Recently, a lncRNA antisense to H19 has been identified and its altered expression in human cancer cell lines.94 The deregulation of this lncRNA in cancer further highlights the complexity of regulation within this gene cluster and may be relevant for CNS tumors.30 Together, these examples demonstrate that lncRNAs are a rich source of candidate genes involved in normal health whose deregulation results in disparate diseases of the central nervous system. Targeting of long noncoding RNAs. RNA knockdown strate- gies. Although the human genome is pervasively transcribed, the overwhelming majority produces non-protein coding transcripts that remain an unexplored field for drug discovery. RNA is a good candidate for drug design because it can adopt secondary structures that allow binding to specific ligands. The first RNA molecule was targeted in the late 1970s95 when a short single- stranded sequence of DNA (antisense oligonucleotide, ASO), was developed to bind and block the translation of Rous sarcoma viral RNA. Since the application of the first unmodified antisense oligonucleotide molecules in 1978, numerous chemical modifi- cations have been tested to improve the drug-like properties of ASOs. ASOs are used to knockdown genes through degradation of their respective mRNAs by RNase H (enzyme that cleaves RNA:RNA or RNA:DNA pairs) and inhibition of the transla- tion process that does not require cleavage by RNase H. Stability, affinity and/or protein binding has been improved by the use of chemical modifications such as phosphorothioate backbones, morpholino oligomers, peptide nucleic acids (PNAs) or locked nucleic acids (LNAs). Multiple RNase H-dependent ASOs are in clinical trials, including a drug for high-grade glioma in Phase IIB trials.96 The discovery of double-stranded small interfering RNAs (siRNAs) in the late 1990s added to the arsenal of RNA- targeting strategies and was successfully used in human cells a few years later.97 The in vivo application of RNA interference to silence a specific transcript has shown promise but is limited by pharmacokinetic considerations and the poor ability of naked 864 rNA Biology volume 9 issue 6