Abstract
Long noncoding RNAs (lncRNAs) are recently defined as thousands of RNA molecules longer than 200 nucleotides and lacking an appreciable open reading frame in mammals. Although lncRNAs lack protein-coding function, they play critical roles in the regulation of almost all the protein-coding genes in a cell at various stages including chromatin modification, transcription and post-transcriptional processing. It is thus not surprising that lncRNAs may be the crucial regulators in the normal development, physiology and pathology. LncRNAs in neuroscience is a novel research field. Interestingly, recent studies have demonstrated that many lncRNAs are highly expressed in brain and their dysregulations occur in neurological disorders. In this review, we describe the current understanding of lncRNAs in neurobiology and neurological diseases including cerebral injury. LncRNAs could be novel biomarkers and could be potential new targets for new drugs for many neurological diseases in the future, although the related studies are still at in the early stages.
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Abarrategui I, Krangel MS (2007) Noncoding transcription controls downstream promoters to regulate T-cell receptor alpha recombination. EMBO J 26(20):4380–4390
Amaral PP, Mattick JS (2008) Noncoding RNA in development. Mamm Genome 19(7–8):454–492
Amaral PP, Neyt C, Wilkins SJ et al (2009) Complex architecture and regulated expression of the Sox2ot locus during vertebrate development. RNA 15(11):2013–2027
Antoniou D, Stergiopoulos A, Politis PK (2014) Recent advances in the involvement of long non-coding RNAs in neural stem cell biology and brain pathophysiology. Front Physiol 5:155
Aprea J, Prenninger S, Dori M et al (2013) Transcriptome sequencing during mouse brain development identifies long non-coding RNAs functionally involved in neurogenic commitment. EMBO J 32(24):3145–3160
Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J (2007) Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318(5851):798–801
Barry G, Briggs JA, Vanichkina DP et al (2014) The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Mol Psychiatry 19(4):486–494
Bartolomei MS, Zemel S, Tilghman SM (1991) Parental imprinting of the mouse H19 gene. Nature 351(6322):153–155
Bernard D, Prasanth KV, Tripathi V et al (2010) A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J 29(18):3082–3093
Bond AM, Vangompel MJ, Sametsky EA et al (2009) Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry. Nat Neurosci 12(8):1020–1027
Bras J, Guerreiro R, Hardy J (2012) Use of next-generation sequencing and other whole-genome strategies to dissect neurological disease. Nat Rev Neurosci 13(7):453–464
Brown CJ, Ballabio A, Rupert JL et al (1991) A gene from the region of the human X inactivation Centre is expressed exclusively from the inactive X chromosome. Nature 349(6304):38–44
Chartier-Harlin MC, Crawford F, Houlden H et al (1991) Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353(6347):844–846
Chodroff RA, Goodstadt L, Sirey TM et al (2010) Long noncoding RNA genes: conservation of sequence and brain expression among diverse amniotes. Genome Biol 11(7):R72
Choi SH, Kim YH, Hebisch M et al (2014) A three-dimensional human neural cell culture model of Alzheimer's disease. Nature 515(7526):274–278
Davey JW, Hohenlohe PA, Etter PD, Boone JQ, Catchen JM, Blaxter ML (2011) Genome-wide genetic marker discovery and genotyping using next-generation sequencing. Nat Rev Genet 12(7):499–510
Dey BK, Mueller AC, Dutta A (2014) Long non-coding RNAs as emerging regulators of differentiation, development, and disease. Transcription 5(4):e944014
Dharap A, Nakka VP, Vemuganti R (2012) Effect of focal ischemia on long noncoding RNAs. Stroke 43(10):2800–2802
Dharap A, Pokrzywa C, Vemuganti R (2013) Increased binding of stroke-induced long non-coding RNAs to the transcriptional corepressors Sin3A and coREST. ASN Neuro 5(4):283–289
Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke Lancet 371(9624):1612–1623
Du Z, Fei T, Verhaak RG et al (2013) Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer. Nat Struct Mol Biol 20(7):908–913
Faghihi MA, Modarresi F, Khalil AM et al (2008) Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nat Med 14(7):723–730
Fantes J, Ragge NK, Lynch SA et al (2003) Mutations in SOX2 cause anophthalmia. Nat Genet 33(4):461–463
Feng J, Bi C, Clark BS, Mady R, Shah P, Kohtz JD (2006) The Evf-2 noncoding RNA is transcribed from the dlx-5/6 ultraconserved region and functions as a dlx-2 transcriptional coactivator. Genes Dev 20(11):1470–1484
Francescatto M, Vitezic M, Heutink P, Saxena A (2014) Brain-specific noncoding RNAs are likely to originate in repeats and may play a role in up-regulating genes in cis. Int J Biochem Cell Biol 54:331–337
French PJ, Bliss TV, O’Connor VN (2001) A novel non-coding RNA abundantly expressed in rat brain. Neuroscience 108(2):207–215
Gao YF, Wang ZB, Zhu T et al (2016) A critical overview of long non-coding RNA in glioma etiology 2016: an update. Tumour Biol 37(11):14403–14413
Gutschner T, Diederichs S (2012) The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol 9(6):703–719
Guttman M, Amit I, Garber M et al (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458(7235):223–227
Han Y, Zhou L, Wu T et al (2016) Downregulation of lncRNA-MALAT1 affects proliferation and the expression of Stemness markers in glioma stem cell line SHG139S. Cell Mol Neurobiol 36(7):1097–1107
Hashimoto-Torii K, Motoyama J, Hui CC, Kuroiwa A, Nakafuku M, Shimamura K (2003) Differential activities of sonic hedgehog mediated by Gli transcription factors define distinct neuronal subtypes in the dorsal thalamus. Mech Dev 120(10):1097–1111
Hirose T, Virnicchi G, Tanigawa A et al (2014) NEAT1 long noncoding RNA regulates transcription via protein sequestration within subnuclear bodies. Mol Biol Cell 25(1):169–183
Ho TT, Zhou N, Huang J et al (2015) Targeting non-coding RNAs with the CRISPR/Cas9 system in human cell lines. Nucleic Acids Res 43(3):e17
Hsu PD, Lander ES, Zhang F (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell 157(6):1262–1278
Hung T, Wang Y, Lin MF et al (2011) Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet 43(7):621–629
Iyengar BR, Choudhary A, Sarangdhar MA, Venkatesh KV, Gadgil CJ, Pillai B (2014) Non-coding RNA interact to regulate neuronal development and function. Front Cell Neurosci 8:47
Johnson R (2012) Long non-coding RNAs in Huntington's disease neurodegeneration. Neurobiol Dis 46(2):245–254
Johnson R, Richter N, Jauch R et al (2010) Human accelerated region 1 noncoding RNA is repressed by REST in Huntington's disease. Physiol Genomics 41(3):269–274
Kang MJ, Abdelmohsen K, Hutchison ER et al (2014) HuD regulates coding and noncoding RNA to induce APP → Aβ processing. Cell Rep 7(5):1401–1409
Kapranov P, Cheng J, Dike S et al (2007) RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316(5830):1484–1488
Kashi K, Henderson L, Bonetti A, Carninci P (2016) Discovery and functional analysis of lncRNAs: methodologies to investigate an uncharacterized transcriptome. Biochim Biophys Acta 1859(1):3–15
Kaur P, Karolina DS, Sepramaniam S, Armugam A, Jeyaseelan K (2014) Expression profiling of RNA transcripts during neuronal maturation and ischemic injury. PLoS One 9(7):e103525
Kealy J, Commins S (2010) Frequency-dependent changes in synaptic plasticity and brain-derived neurotrophic factor (BDNF) expression in the CA1 to perirhinal cortex projection. Brain Res 1326:51–61
Kondrashov AV, Kiefmann M, Ebnet K, Khanam T, Muddashetty RS, Brosius J (2005) Inhibitory effect of naked neural BC1 RNA or BC200 RNA on eukaryotic in vitro translation systems is reversed by poly(a)-binding protein (PABP). J Mol Biol 353(1):88–103
Korneev SA, Korneeva EI, Lagarkova MA, Kiselev SL, Critchley G, O'Shea M (2008) Novel noncoding antisense RNA transcribed from human anti-NOS2A locus is differentially regulated during neuronal differentiation of embryonic stem cells. RNA 14(10):2030–2037
Kretz M, Siprashvili Z, Chu C et al (2013) Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature 493(7431):231–235
Lewejohann L, Skryabin BV, Sachser N et al (2004) Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice. Behav Brain Res 154(1):273–289
Li S, Tighe SW, Nicolet CM et al (2014) Multi-platform assessment of transcriptome profiling using RNA-seq in the ABRF next-generation sequencing study. Nat Biotechnol 32(9):915–925
Li J, Bian EB, He XJ et al (2016) Epigenetic repression of long non-coding RNA MEG3 mediated by DNMT1 represses the p53 pathway in gliomas. Int J Oncol 48(2):723–733
Lin D, Pestova TV, Hellen CU, Tiedge H (2008) Translational control by a small RNA: dendritic BC1 RNA targets the eukaryotic initiation factor 4A helicase mechanism. Mol Cell Biol 28(9):3008–3019
Lipovich L, Tarca AL, Cai J et al (2014) Developmental changes in the transcriptome of human cerebral cortex tissue: long noncoding RNA transcripts. Cereb Cortex 24(6):1451–1459
Liu T, Huang Y, Chen J et al (2014) Attenuated ability of BACE1 to cleave the amyloid precursor protein via silencing long noncoding RNA BACE1-AS expression. Mol Med Rep 10(3):1275–1281
Liu SJ, Nowakowski TJ, Pollen AA et al (2016) Single-cell analysis of long non-coding RNAs in the developing human neocortex. Genome Biol 17:67
Lynch G, Kramar EA, Rex CS et al (2007) Brain-derived neurotrophic factor restores synaptic plasticity in a knock-in mouse model of Huntington's disease. J Neurosci 27(16):4424–4434
Lyons SM, Achorn C, Kedersha NL, Anderson PJ, Ivanov P (2016) YB-1 regulates tiRNA-induced stress granule formation but not translational repression. Nucleic Acids Res 44(14):6949–6960
Ma J, Wang P, Yao Y et al (2016) Knockdown of long non-coding RNA MALAT1 increases the blood-tumor barrier permeability by up-regulating miR-140. Biochim Biophys Acta 1859(2):324–338
Mattick JS (2001) Non-coding RNAs: the architects of eukaryotic complexity. EMBO Rep 2(11):986–991
Mattson MP (2004) Pathways towards and away from Alzheimer's disease. Nature 430(7000):631–639
Mehler MF, Mattick JS (2007) Noncoding RNAs and RNA editing in brain development, functional diversification, and neurological disease. Physiol Rev 87(3):799–823
Mercer TR, Dinger ME, Sunkin SM, Mehler MF, Mattick JS (2008) Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A 105(2):716–721
Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10(3):155–159
Mercer TR, Wilhelm D, Dinger ME et al (2011) Expression of distinct RNAs from 3′ untranslated regions. Nucleic Acids Res 39(6):2393–2403
Meredith EK, Balas MM, Sindy K, Haislop K, Johnson AM (2016) An RNA matchmaker protein regulates the activity of the long noncoding RNA HOTAIR. RNA 22(7):995–1010
Meyer CA, Liu XS (2014) Identifying and mitigating bias in next-generation sequencing methods for chromatin biology. Nat Rev Genet 15(11):709–721
Meyer NP, Roelink H (2003) The amino-terminal region of Gli3 antagonizes the Shh response and acts in dorsoventral fate specification in the developing spinal cord. Dev Biol 257(2):343–355
Mineo M, Ricklefs F, Rooj AK et al (2016) The long non-coding RNA HIF1A-AS2 facilitates the maintenance of mesenchymal glioblastoma stem-like cells in hypoxic niches. Cell Rep 15(11):2500–2509
Miyoshi N, Wagatsuma H, Wakana S et al (2000) Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, first mapped on mouse distal chromosome 12 and human chromosome 14q. Genes Cells 5(3):211–220
Modarresi F, Faghihi MA, Lopez-Toledano MA et al (2012) Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol 30(5):453–459
Mus E, Hof PR, Tiedge H (2007) Dendritic BC200 RNA in aging and in Alzheimer's disease. Proc Natl Acad Sci U S A 104(25):10679–10684
Ng SY, Johnson R, Stanton LW (2012) Human long non-coding RNAs promote pluripotency and neuronal differentiation by association with chromatin modifiers and transcription factors. EMBO J 31(3):522–533
Ørom UA, Derrien T, Beringer M et al (2010) Long noncoding RNAs with enhancer-like function in human cells. Cell 143(1):46–58
Pang KC, Dinger ME, Mercer TR et al (2009) Genome-wide identification of long noncoding RNAs in CD8+ T cells. J Immunol 182(12):7738–7748
Pastori C, Kapranov P, Penas C et al (2015) The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation. Proc Natl Acad Sci U S A 112(27):8326–8331
Pollard KS, Salama SR, Lambert N et al (2006) An RNA gene expressed during cortical development evolved rapidly in humans. Nature 443(7108):167–172
Ponjavic J, Oliver PL, Lunter G, Ponting CP (2009) Genomic and transcriptional co-localization of protein-coding and long non-coding RNA pairs in the developing brain. PLoS Genet 5(8):e1000617
Ponting CP, Oliver PL, Reik W (2009) Evolution and functions of long noncoding RNAs. Cell 136(4):629–641
Qureshi IA, Mehler MF (2012) Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease. Nat Rev Neurosci 13(8):528–541
Qureshi IA, Mehler MF (2013) Long non-coding RNAs: novel targets for nervous system disease diagnosis and therapy. Neurotherapeutics 10(4):632–646
Qureshi IA, Mattick JS, Mehler MF (2010) Long non-coding RNAs in nervous system function and disease. Brain Res 1338:20–35
Ramos AD, Diaz A, Nellore A et al (2013) Integration of genome-wide approaches identifies lncRNAs of adult neural stem cells and their progeny in vivo. Cell Stem Cell 12(5):616–628
Ramos AD, Andersen RE, Liu SJ et al (2015) The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells. Cell Stem Cell 16(4):439–447
Rapicavoli NA, Poth EM, Blackshaw S (2010) The long noncoding RNA RNCR2 directs mouse retinal cell specification. BMC Dev Biol 10:49
Santoro M, Nociti V, Lucchini M, De Fino C, Losavio FA, Mirabella M (2016) Expression profile of long non-coding RNAs in serum of patients with multiple sclerosis. J Mol Neurosci 59(1):18–23
Sauvageau M, Goff LA, Lodato S et al (2013) Multiple knockout mouse models reveal lincRNAs are required for life and brain development. Elife 2:e01749
Selkoe DJ (2002) Alzheimer's disease is a synaptic failure. Science 298(5594):789–791
Shechner DM, Hacisuleyman E, Younger ST, Rinn JL (2015) Multiplexable, locus-specific targeting of long RNAs with CRISPR-display. Nat Methods 12(7):664–670
Shi Y, Wang Y, Luan W et al (2014) Long non-coding RNA H19 promotes glioma cell invasion by deriving miR-675. PLoS One 9(1):e86295
Shimojo M (2008) Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150 glued. J Biol Chem 283(50):34880–34886
Smalheiser NR (2014) The RNA-centred view of the synapse: non-coding RNAs and synaptic plasticity. Philos Trans R Soc Lond B Biol Sci 369(1652). doi:10.1098/rstb.2013.0504
Sone M, Hayashi T, Tarui H, Agata K, Takeichi M, Nakagawa S (2007) The mRNA-like noncoding RNA Gomafu constitutes a novel nuclear domain in a subset of neurons. J Cell Sci 120(Pt 15):2498–2506
Soreq L, Guffanti A, Salomonis N et al (2014) Long non-coding RNA and alternative splicing modulations in Parkinson's leukocytes identified by RNA sequencing. PLoS Comput Biol 10(3):e1003517
Taft RJ, Pang KC, Mercer TR, Dinger M, Mattick JS (2010) Non-coding RNAs: regulators of disease. J Pathol 220(2):126–139
The ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489(7414):57–74
Tochitani S, Hayashizaki Y (2008) Nkx2.2 antisense RNA overexpression enhanced oligodendrocytic differentiation. Biochem Biophys Res Commun 372(4):691–696
Tsuang MT, Taylor L, Faraone SV (2004) An overview of the genetics of psychotic mood disorders. J Psychiatr Res 38(1):3–15
Ulitsky I, Shkumatava A, Jan CH, Sive H, Bartel DP (2011) Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell 147(7):1537–1550
Vassallo I, Zinn P, Lai M, Rajakannu P, Hamou MF, Hegi ME (2016) WIF1 re-expression in glioblastoma inhibits migration through attenuation of non-canonical WNT signaling by downregulating the lncRNA MALAT1. Oncogene 35(1):12–21
Wang H, Iacoangeli A, Popp S et al (2002) Dendritic BC1 RNA: functional role in regulation of translation initiation. J Neurosci 22(23):10232–10241
Wang Z, Gerstein M, Snyder M (2009b) RNA-seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10(1):57–63
Wang Q, Peng Y, Chen S et al (2009a) Pretreatment with electroacupuncture induces rapid tolerance to focal cerebral ischemia through regulation of endocannabinoid system. Stroke 40(6):2157–2164
Wang P, Ren Z, Sun P (2012) Overexpression of the long non-coding RNA MEG3 impairs in vitro glioma cell proliferation. J Cell Biochem 113(6):1868–1874
Wilusz JE, Sunwoo H, Spector DL (2009) Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 23(13):1494–1504
Wu P, Zuo X, Deng H, Liu X, Liu L, Ji A (2013) Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases. Brain Res Bull 97:69–80
Xie H, Leung KL, Chen L et al (2010) Brain-derived neurotrophic factor rescues and prevents chronic intermittent hypoxia-induced impairment of hippocampal long-term synaptic plasticity. Neurobiol Dis 40(1):155–162
Yang X, Gao L, Guo X et al (2014) A network based method for analysis of lncRNA-disease associations and prediction of lncRNAs implicated in diseases. PLoS One 9(1):e87797
Young RS, Marques AC, Tibbit C et al (2012) Identification and properties of 1,119 candidate lincRNA loci in the Drosophila melanogaster genome. Genome Biol Evol 4(4):427–442
Zalfa F, Adinolfi S, Napoli I et al (2005) Fragile X mental retardation protein (FMRP) binds specifically to the brain cytoplasmic RNAs BC1/BC200 via a novel RNA-binding motif. J Biol Chem 280(39):33403–33410
Zhang X, Rice K, Wang Y et al (2010) Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions. Endocrinology 151(3):939–947
Zhang JX, Han L, Bao ZS et al (2013) HOTAIR, a cell cycle-associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma. Neuro-Oncology 15(12):1595–1603
Zhang J, Yuan L, Zhang X et al (2016c) Altered long non-coding RNA transcriptomic profiles in brain microvascular endothelium after cerebral ischemia. Exp Neurol 277:162–170
Zhang F, Gao C, Ma XF et al (2016a) Expression profile of long noncoding RNAs in peripheral blood mononuclear cells from multiple sclerosis patients. CNS Neurosci Ther 22(4):298–305
Zhang F, Liu G, Wei C, Gao C, Hao J (2016b) Linc-MAF-4 regulates Th1/Th2 differentiation and is associated with the pathogenesis of multiple sclerosis by targeting MAF. FASEB J. doi:10.1096/fj.201600838R
Zhao F, Qu Y, Liu J et al (2015) Microarray profiling and Co-expression network analysis of LncRNAs and mRNAs in neonatal rats following hypoxic-ischemic brain damage. Sci Rep 5:13850
Ziats MN, Rennert OM (2013) Aberrant expression of long noncoding RNAs in autistic brain. J Mol Neurosci 49(3):589–593
Acknowledgments
This work was supported by National Natural Science Foundation of China (No.81301055 and No.81271478), partly by Educational Scientific Research Projects of Sichuan Province (No.13ZB0273). We would like to thank Pro. Chunxiang Zhang for his excellent assistance.
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Chen, Y., Zhou, J. LncRNAs: macromolecules with big roles in neurobiology and neurological diseases. Metab Brain Dis 32, 281–291 (2017). https://doi.org/10.1007/s11011-017-9965-8
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DOI: https://doi.org/10.1007/s11011-017-9965-8