Brain Research Bulletin 97 (2013) 69–80 Contents lists available at ScienceDirect Brain Research Bulletin jo urnal homepage: www.elsevier.com/locate/brainresbull Review Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases 1 1 ∗ Ping Wu , Xialin Zuo , Houliang Deng, Xiaoxia Liu, Li Liu, Aimin Ji Center for Drug Research and Development, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, PR China a r t i c l e i n f o a b s t r a c t Article history: Long noncoding RNAs (lncRNAs) have been attracting immense research interest, while only a handful of Received 25 February 2013 lncRNAs have been characterized thoroughly. Their involvement in the fundamental cellular processes Received in revised form 31 May 2013 including regulate gene expression at epigenetics, transcription, and post-transcription highlighted a cen- Accepted 1 June 2013 tral role in cell homeostasis. However, lncRNAs studies are still at a relatively early stage, their definition, Available online 10 June 2013 conservation, functions, and action mechanisms remain fairly complicated. Here, we give a systematic and comprehensive summary of the existing knowledge of lncRNAs in order to provide a better under- Keywords: standing of this new studying field. lncRNAs play important roles in brain development, neuron function Expression signature lncRNA and maintenance, and neurodegenerative diseases are becoming increasingly evident. In this review, we also highlighted recent studies related lncRNAs in central nervous system (CNS) development and Noncoding RNA Neuron neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s Neurodegenerative disease disease (HD) and amyotrophic lateral sclerosis (ALS), and elucidated some specific lncRNAs which may be important for understanding the pathophysiology of neurodegenerative diseases, also have the potential as therapeutic targets. © 2013 Elsevier Inc. All rights reserved. Contents 1. Introduction . 70 2. Biology of lncRNAs . 70 2.1. Definition of lncRNAs. 70 2.2. Evolution or conservation . 71 2.3. Function or transcription noise . 71 2.4. Stability . 71 Abbreviations: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; A␤42, amyloid-␤-42; A␤40, amyloid-␤-40; APP, amyloid precursor protein; BACE1, ␤- site amyloid precursor protein-cleaving enzyme; BC200 (BCYRN1), brain cytoplasmic RNA 1; BC1, brain cytoplasmic RNA 1; BDNF, brain derived neurotrophic factor; BRIC–Seq, 5 -bromo-uridine immunoprecipitation chase followed by deep sequencing; Camk2n1, calcium/calmodulin-dependent protein kinase II inhibitor 1; CaMKII, 2+ Ca /calmodulin-dependent protein kinase II; catRAPID, fast predictions of RNA and protein interactions and domains; CHIRP-Seq, chromatin isolation by RNA purification followed by deep sequencing; CNS, central nervous system; c-KLAN, combined knockdown and localization analysis of noncoding RNAs; DJ-1 (PARK7), Parkinson disease protein 7; eIF4A, eukaryotic initiation factor 4A; ENORs, expressed noncoding regions; FUS/TLS, fused in sarcoma/translated in liposarcoma; Gad1, glutamate decarboxylase 1; GDNFOS, glial cell derived neurotrophic factor opposite strand; HAR1, human accelerated regions 1; HGNCHOTAIRM1, HOX antisense intergenic RNA myeloid 1; HUGO, Gene Nomenclature Committee; HD, Huntington’s disease; HTTAS, Huntingtin antisense; iPSC, induced pluripotent stem cells; ISH, in situ hybridization; lincRNAs, large intergenic noncoding RNAs; lncRNAs, long noncoding RNAs; LTD, long-term depression; LTP, long-term potentiation; LRRK2, leucine-rich repeat kinase 2; Malat1, metastasis- associated lung adenocarcinoma transcript 1; NAT-Rad18, natural antisense-Rad 18; ncRNAs, noncoding RNAs; Nkx2.2 AS, Nkx2.2 antisense; NO, Nitric oxide; NOSs, nitric oxide synthases; Nrgn, neurogranin; NTAs, natural antisense RNAs; ORF, open reading frame; PCG, protein coding gene; PD, Parkinson’s disease; PINK1, phosphatase and tensin homologue induced putative kinase 1; PRC2, polycomb repressive complex 2; REST/NRSF, RE1-silencing transcription factor/neuron-restrictive silencer factor; RIP- Chip, RNP immunoprecipitation-microarray; RNCR2, retinal noncoding RNA 2; SAGE, serial analysis of gene expression; Shh, sonic hedgehog; Six3OS, Six3 opposite strand; SOX2, SRY (sex determining region Y)-box 2; Sox2OT, Sox2 overlapping transcript; TDP43TAR, DNA-binding domain protein 43; TUG1, taurine upregulated gene 1; wtSOD1, wilde type Cu/Zn superoxide dismutase; Xist, X-inactive specific transcript. ∗ Corresponding author. Tel.: +86 02061643500. E-mail addresses: aiminji [email protected], [email protected] (A. Ji). 1 The authors contributed equally to this work and should each be considered co-first author. 0361-9230/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brainresbull.2013.06.001 70 P. Wu et al. / Brain Research Bulletin 97 (2013) 69–80 2.5. lncRNA classification and subgroup . 71 2.6. How lncRNAs play function and the possible roles of lncRNAs. 72 3. lncRNAs in the central nervous system . 72 3.1. lncRNAs in brain development . 72 3.2. LlncRNAs in neural differentiation and maintenance. 73 3.3. lncRNAs in synaptic plasticity, cognitive function and memory . 74 3.4. lncRNAs in aged brain and neurodegenerative disorders. 74 3.4.1. Dysregulated lncRNAs in Alzheimer’s disease . 76 3.4.2. Dysregulation of lncRNAs in Parkinson’s disease . 76 3.4.3. Dysregulation of lncRNAs in Huntington’s disease . 76 3.4.4. Dysregulation of lncRNAs in amyotrophic lateral sclerosis . 77 4. Perspective and challenge . 77 Acknowledgements . 77 References . 77 1. Introduction 2. Biology of lncRNAs Over the last decade, advances in genome-wide analysis of 2.1. Definition of lncRNAs the eukaryotic transcriptome have revealed that up to 90% of the human genome are transcribed, however, GENCODE-annotated The initial lncRNAs, such as XIST (X-inactive specific tran- exons of protein-coding genes only cover 2.94% the genome, while script) and H19 were first discovered by searching cDNA libraries the remaining are transcribed as noncoding RNAs (ncRNAs) (ENC for clones in 1980s and 1990s (Brown et al., 1991; Bartolomei Project and Consortium, 2012). Noncoding transcripts are further et al., 1991). With the improvement of microarray sensitivity and divided into housekeeping ncRNAs and regulatory ncRNAs. House- sequencing technology, an abundance of lncRNAs transcripts have keeping ncRNAs, which are usually considered constitutive, include been found (Kapranov et al., 2007). However, unlike miRNAs, as ribosomal, transfer, small nuclear and small nucleolar RNAs. Reg- lacking of uniform systematic annotation systems cause the same ulatory ncRNAs are generally divided into two classes based on lncRNAs with different names in science literatures, which increase nucleotide length. Those less than 200 nucleotides are usually the difficulty to retrieve and integrate the study results. referred to as short/small ncRNAs, including microRNAs (miRNAs), As the increasing acquaintance of lncRNAs, defining lncRNAs small interfering RNAs and Piwi-associated RNAs, and those greater simply based on nucleotide size (>200 nt) and lack of capability than 200 bases are known as long noncoding RNAs (lncRNAs) of protein-coding more than 100 amino acids is far from scientific (Nagano and Fraser, 2011). in intellectually. First, the cutoff of 200 nucleotides is arbitrarily The crucial role of miRNAs in post-transcriptional gene chosen limited by the current RNA purification protocols, taking no regulation by repressing gene expression via targeting semi- consideration of the functional meaning (Kapranov et al., 2007). The complementary motifs in target mRNAs has been highlighted (Lee second unreasonable is the protein-coding ability. As we know, the et al., 1993). An abundance of studies showed the disrupted miRNAs Protein Coding Gene (PCG) is defined as a transcript that contains in cancer (Liu et al., 2012), stroke (Wu et al., 2012), neurologi- an open reading frame (ORF) longer than 100 amino acids (Dinger cal diseases (Bian and Sun, 2011), suggesting the miRNAs must et al., 2008a). However, studies have found lncRNAs can contain play some roles in disease pathologic process, diagnosis, progno- ORFs longer than 100 amino acids but unnecessarily synthesize sis, and also with the potential as promising treatment targets. to polypeptides, in addition, polypeptides shorter than 100 amino lncRNAs have been attracting intense interest with the attractive acids can also be functional in organisms as peptide (Washietl et al., possibility to find new molecules and mechanisms that could shed 2011). Studies have demonstrated that the same RNA can be spliced light on the explanation of organismal complexity and complex into different alterations play the PCGs functions or non-coding diseases. functions (Candeias et al., 2008; Martick et al., 2008; Poliseno et al., The central nervous system (CNS) is the most highly evolved 2010). It is clear that the strict dichotomy between protein-coding and sophisticated biological system. It is comprised of an enormous and non-coding transcripts is unadvisable. array of neuron and glial cell subtypes which distributed at the Given the aforementioned limitations, one updated definition strict and precise region, forming into dynamic neural networks describes lncRNAs as RNA molecules that may function as either responding with internal signal and external stimulation, then primary or spliced transcripts and not belong