surface enables encapsulation of a range of cargos and provides an intrinsic mechanism for targeting dendritic cells, macrophages and tumor cells.130-133 Essential components of the immune system such as macro- phages can potentially be engineered to deliver therapeutic mol- ecules due to their tendency to phagocytose nanoparticles and to target diseased tissues.134,135 Advances in the field of nano- technology have led to preclinical studies in which ex-vivo-made nanoparticle-bearing macrophages are re-injected into the body as “Trojan horse” delivery carriers.136 In this context, the forma- tion of siRNA and/or oligonucleotide nanoparticles is a interest- ing strategy for systemic nucleic acid delivery. Conclusions It is becoming abundantly clear that focusing drug discovery efforts solely on conventional protein targets may not produce the therapeutics needed urgently to combat CNS disorders. The last decade has yielded much insight into the important func- tional role of noncoding RNAs as well as the mechanisms of action of these transcripts. The direct involvement of long non- coding RNAs in the regulation of basic biological processes leads us to hypothesize that their altered expression and/or function can have profound effects on multiple cellular pathways and that they may constitute a large new class of viable biomarker and drug targets. Acknowledgements The authors are grateful to all colleagues who gave helpful com- ments and proofread the manuscript. Our work on long non- coding RNA mechanisms in CNS disorders is in part funded by the US. National Institutes of Health (5R01NS063974 and 5R01MH084880). References 1. Seila AC, Calabrese JM, Levine SS, Yeo GW, Rahl PB, Flynn RA, et al. Divergent transcription from active pro- moters. Science 2008; 322:1849-51; PMID:19056940; http://dx.doi.org/10.1126/science.1162253. 2. Preker P, Nielsen J, Kammler S, Lykke-Andersen S, Christensen MS, Mapendano CK, et al. RNA exosome depletion reveals transcription upstream of active human promoters. Science 2008; 322:1851- 4; PMID:19056938; http://dx.doi.org/10.1126/sci- ence.1164096. 3. Pandey RR, Mondal T, Mohammad F, Enroth S, Redrup L, Komorowski J, et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcrip- tional silencing through chromatin-level regulation. Mol Cell 2008; 32:232-46; PMID:18951091; http:// dx.doi.org/10.1016/j.molcel.2008.08.022. 4. Nagano T, Mitchell JA, Sanz LA, Pauler FM, Ferguson- Smith AC, Feil R, et al. The Air noncoding RNA epige- netically silences transcription by targeting G9a to chro- matin. Science 2008; 322:1717-20; PMID:18988810; http://dx.doi.org/10.1126/science.1163802. 5. He Y, Vogelstein B, Velculescu VE, Papadopoulos N, Kinzler KW. The antisense transcriptomes of human cells. Science 2008; 322:1855-7; PMID:19056939; http://dx.doi.org/10.1126/science.1163853. 6. Finocchiaro G, Carro MS, Francois S, Parise P, DiNinni V, Muller H. Localizing hotspots of antisense transcription. Nucleic Acids Res 2007; 35:1488-500; PMID:17284453; http://dx.doi.org/10.1093/nar/ gkm027. 7. Core LJ, Lis JT. Transcription regulation through promoter-proximal pausing of RNA polymerase II. Science 2008; 319:1791-2; PMID:18369138; http:// dx.doi.org/10.1126/science.1150843. 8. Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, et al. RNA maps reveal new RNA classes and a possible function for pervasive transcrip- tion. Science 2007; 316:1484-8; PMID:17510325; http://dx.doi.org/10.1126/science.1138341. 9. Ladd PD, Smith LE, Rabaia NA, Moore JM, Georges SA, Hansen RS, et al. An antisense transcript span- ning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals. Hum Mol Genet 2007; 16:3174-87; PMID:17921506; http://dx.doi.org/10.1093/hmg/ ddm293. 10. Khalil AM, Faghihi MA, Modarresi F, Brothers SP, Wahlestedt C. A novel RNA transcript with antiapop- totic function is silenced in fragile X syndrome. PLoS One 2008; 3:1486; PMID:18213394; http://dx.doi. org/10.1371/journal.pone.0001486. 11. Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 2009; 458:223-7; PMID:19182780; http://dx.doi.org/10.1038/nature07672. 12. Amaral PP, Clark MB, Gascoigne DK, Dinger ME, Mattick JS. lncRNAdb: a reference database for long noncoding RNAs. Nucleic Acids Res 2011; 39:146- 51; PMID:21112873; http://dx.doi.org/10.1093/nar/ gkq1138. 13. Munroe SH, Lazar MA. Inhibition of c-erbA mRNA splicing by a naturally occurring antisense RNA. J BiolChem 1991; 266:22083-6; PMID:1657988. 14. Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, et al. Expression of a non- coding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase. Nat Med 2008; 14:723-30; PMID:18587408; http:// dx.doi.org/10.1038/nm1784. 15. Mercer TR, Dinger ME, Mattick JS. Long non- coding RNAs: insights into functions. Nat Rev Genet 2009; 10:155-9; PMID:19188922; http://dx.doi. org/10.1038/nrg2521. 16. Feng J, Bi C, Clark BS, Mady R, Shah P, Kohtz JD. The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev 2006; 20:1470- 84; PMID:16705037; http://dx.doi.org/10.1101/ gad.1416106. 17. Martianov I, Ramadass A, Serra Barros A, Chow N, Akoulitchev A. Repression of the human dihydrofolat- ereductase gene by a non-coding interfering transcript. Nature 2007; 445:666-70; PMID:17237763; http:// dx.doi.org/10.1038/nature05519. 18. Wang X, Arai S, Song X, Reichart D, Du K, Pascual G, et al. Induced ncRNAsallosterically modify RNA- binding proteins in cis to inhibit transcription. Nature 2008; 454:126-30; PMID:18509338; http://dx.doi. org/10.1038/nature06992. 19. Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, et al. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 2008; 451:202-6; PMID:18185590; http://dx.doi. org/10.1038/nature06468. 20. Yap KL, Li S, Muñoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell 2010; 38:662-74; PMID:20541999; http:// dx.doi.org/10.1016/j.molcel.2010.03.021. 21. Morris KV, Santoso S, Turner AM, Pastori C, Hawkins PG. Bidirectional transcription directs both transcrip- tional gene activation and suppression in human cells. PLoS Genet 2008; 4:1000258; PMID:19008947; http://dx.doi.org/10.1371/journal.pgen.1000258. 22. Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci USA 2009; 106:11667-72; PMID:19571010; http://dx.doi.org/10.1073/pnas.0904715106. 23. Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 2007; 129:1311- 23; PMID:17604720; http://dx.doi.org/10.1016/j. cell.2007.05.022. 24. Gräff J, Kim D, Dobbin MM, Tsai LH. Epigenetic regulation of gene expression in physiological and path- ological brain processes. Physiol Rev 2011; 91:603-49; PMID:21527733; http://dx.doi.org/10.1152/phys- rev.00012.2010. 25. Mercer TR, Dinger ME, Mariani J, Kosik KS, Mehler MF, Mattick JS. Noncoding RNAs in Long-Term Memory Formation. Neuroscientist 2008; 14:434-45; PMID:18997122; http://dx.doi. org/10.1177/1073858408319187. 26. Bernard D, Prasanth KV, Tripathi V, Colasse S, Nakamura T, Xuan Z, et al. A long nuclear-retained non-coding RNA regulates synaptogenesis by modu- lating gene expression. EMBO J 2010; 29:3082- 93; PMID:20729808; http://dx.doi.org/10.1038/ emboj.2010.199. 27. Pollard KS, Salama SR, Lambert N, Lambot MA, Coppens S, Pedersen JS, et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature 2006; 443:167-72; PMID:16915236; http://dx.doi.org/10.1038/nature05113. 28. Mehler MF, Mattick JS. Non-coding RNAs in the nervous system. J Physiol 2006; 575:333-41; PMID:16809366; http://dx.doi.org/10.1113/jphysi- ol.2006.113191. 29. Mercer TR, Qureshi IA, Gokhan S, Dinger ME, Li G, Mattick JS, et al. Long noncoding RNAs in neuronal-glial fate specification and oligodendro- cyte lineage maturation. BMC Neurosci 2010; 11:14; PMID:20137068; http://dx.doi.org/10.1186/1471- 2202-11-14. 30. Qureshi IA, Mattick JS, Mehler MF. Long non- coding RNAs in nervous system function and disease. Brain Res 2010; 1338:20-35; PMID:20380817; http:// dx.doi.org/10.1016/j.brainres.2010.03.110. www.landesbioscience.com rNA Biology 867