Emerging Roles for Long Non-Coding RNAs in Cancer and Neurological Disorders

The recent discovery of thousands of long non-coding (lnc)RNAs in the human genome has prompted investigation of the potential roles of these molecules in human biology and medicine. Indeed, it is now well documented that many lncRNAs are involved in key biological processes, including dosage compensation, genomic imprinting, chromatin regulation, alternative splicing of pre-mRNA, nuclear organization; and potentially many other biological processes, which are yet to be elucidated. Recently, a number of studies have also reported that lncRNAs are dysregulated in a number of human diseases, including several cancers and neurological disorders. Although many of these studies have fallen short of implicating lncRNAs as causative, they suggest potential roles that warrant further in depth investigations. In this review, we discuss the current state of knowledge regarding the roles of lncRNAs in cancer and neurological disorders, and suggest potential future directions in this rapidly emerging field.

[1]  Anne Gallagher,et al.  Fragile X-associated disorders: a clinical overview , 2012, Journal of Neurology.

[2]  H. Lodish,et al.  Long noncoding RNA-mediated anti-apoptotic activity in murine erythroid terminal differentiation. , 2011, Genes & development.

[3]  Howard Y. Chang,et al.  Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. , 2011, Molecular cell.

[4]  I. Bièche,et al.  Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. , 2011, Journal of the National Cancer Institute.

[5]  Pieter C. Dorrestein,et al.  ncRNA- and Pc2 Methylation-Dependent Gene Relocation between Nuclear Structures Mediates Gene Activation Programs , 2011, Cell.

[6]  S. Miyano,et al.  Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. , 2011, Cancer research.

[7]  D. Cacchiarelli,et al.  A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA , 2011, Cell.

[8]  Peter A. Jones,et al.  A decade of exploring the cancer epigenome — biological and translational implications , 2011, Nature Reviews Cancer.

[9]  Howard Y. Chang,et al.  Molecular mechanisms of long noncoding RNAs. , 2011, Molecular cell.

[10]  Cole Trapnell,et al.  Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. , 2011, Genes & development.

[11]  D. Girelli,et al.  A polymorphism in the chromosome 9p21 ANRIL locus is associated to Philadelphia positive acute lymphoblastic leukemia. , 2011, Leukemia research.

[12]  J. Rinn,et al.  lincRNAs act in the circuitry controlling pluripotency and differentiation , 2011, Nature.

[13]  Jeannie T. Lee,et al.  YY1 Tethers Xist RNA to the Inactive X Nucleation Center , 2011, Cell.

[14]  Ahmad M Khalil,et al.  RNA-protein interactions in human health and disease. , 2011, Seminars in cell & developmental biology.

[15]  Howard Y. Chang,et al.  Long noncoding RNAs and human disease. , 2011, Trends in cell biology.

[16]  J. Mattick,et al.  The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion. , 2011, Cancer research.

[17]  Howard Y. Chang,et al.  Extensive and coordinated transcription of noncoding RNAs within cell cycle promoters , 2011, Nature Genetics.

[18]  T. Hudson.  Cancer genome variation in children, adolescents, and young adults , 2011, Cancer.

[19]  M. Kitagawa,et al.  Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15INK4B tumor suppressor gene , 2011, Oncogene.

[20]  B. Ray,et al.  Autism, Alzheimer disease, and fragile X , 2011, Neurology.

[21]  Haiyang Xie,et al.  Overexpression of Long Non-coding RNA HOTAIR Predicts Tumor Recurrence in Hepatocellular Carcinoma Patients Following Liver Transplantation , 2011, Annals of Surgical Oncology.

[22]  Zhenhua Li,et al.  ncRAN, a newly identified long noncoding RNA, enhances human bladder tumor growth, invasion, and survival. , 2011, Urology.

[23]  I. Bièche,et al.  ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  Yusuke Nakamura,et al.  Association of a novel long non‐coding RNA in 8q24 with prostate cancer susceptibility , 2011, Cancer science.

[25]  D. Selkoe.  Alzheimer's disease. , 2011, Cold Spring Harbor perspectives in biology.

[26]  Toshiro K. Ohsumi,et al.  Genome-wide identification of polycomb-associated RNAs by RIP-seq. , 2010, Molecular cell.

[27]  K. Double,et al.  Selective cell death in neurodegeneration: Why are some neurons spared in vulnerable regions? , 2010, Progress in Neurobiology.

[28]  J. Gil,et al.  Epigenetic regulation of the INK4b-ARF-INK4a locus , 2010, Epigenetics.

[29]  J. Manley,et al.  Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. , 2010, Genes & development.

[30]  B. Blencowe,et al.  The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. , 2010, Molecular cell.

[31]  Howard Y. Chang,et al.  Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes , 2010, Science.

[32]  J. Rinn,et al.  A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response , 2010, Cell.

[33]  S. Raguz,et al.  Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. , 2010, Molecular cell.

[34]  David I. Smith,et al.  Identification of long stress-induced non-coding transcripts that have altered expression in cancer. , 2010, Genomics.

[35]  Howard Y. Chang,et al.  Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis , 2010, Nature.

[36]  D. Loesch,et al.  Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio. , 2010, Human molecular genetics.

[37]  P. Wong,et al.  The β-Secretase Enzyme BACE in Health and Alzheimer's Disease: Regulation, Cell Biology, Function, and Therapeutic Potential , 2009, The Journal of Neuroscience.

[38]  T. Ebner,et al.  RNA Gain-of-Function in Spinocerebellar Ataxia Type 8 , 2009, PLoS genetics.

[39]  J. Rinn,et al.  Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression , 2009, Proceedings of the National Academy of Sciences.

[40]  M. Ohira,et al.  High expression of ncRAN, a novel non-coding RNA mapped to chromosome 17q25.1, is associated with poor prognosis in neuroblastoma. , 2009, International journal of oncology.

[41]  Ludovico Minati,et al.  Reviews: Current Concepts in Alzheimer's Disease: A Multidisciplinary Review , 2009, American journal of Alzheimer's disease and other dementias.

[42]  Michael F. Lin,et al.  Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals , 2009, Nature.

[43]  K. Kinzler,et al.  The Antisense Transcriptomes of Human Cells , 2008, Science.

[44]  Jeannie T. Lee,et al.  Polycomb Proteins Targeted by a Short Repeat RNA to the Mouse X Chromosome , 2008, Science.

[45]  J. Komorowski,et al.  Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. , 2008, Molecular cell.

[46]  T. Morgan,et al.  Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase , 2008, Nature Medicine.

[47]  R. Aharonov,et al.  MicroRNAs accurately identify cancer tissue origin , 2008, Nature Biotechnology.

[48]  David I. Smith,et al.  Long, abundantly expressed non-coding transcripts are altered in cancer. , 2008, Human molecular genetics.

[49]  Lin Zhang,et al.  The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis , 2008, Nature Cell Biology.

[50]  C. Wahlestedt,et al.  A Novel RNA Transcript with Antiapoptotic Function Is Silenced in Fragile X Syndrome , 2008, PloS one.

[51]  S. Sunkin,et al.  Specific expression of long noncoding RNAs in the mouse brain , 2008, Proceedings of the National Academy of Sciences.

[52]  S. Tapscott,et al.  An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals. , 2007, Human molecular genetics.

[53]  Sek Won Kong,et al.  Altered microRNA expression in human heart disease. , 2007, Physiological genomics.

[54]  W. Cho.  OncomiRs: the discovery and progress of microRNAs in cancers , 2007, Molecular Cancer.

[55]  S. Warren,et al.  The pathophysiology of fragile x syndrome. , 2007, Annual review of genomics and human genetics.

[56]  M. Swanson,et al.  Muscleblind-like 1 interacts with RNA hairpins in splicing target and pathogenic RNAs , 2007, Nucleic acids research.

[57]  Howard Y. Chang,et al.  Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs , 2007, Cell.

[58]  P. Hof,et al.  Dendritic BC200 RNA in aging and in Alzheimer's disease , 2007, Proceedings of the National Academy of Sciences.

[59]  I. Bièche,et al.  Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. , 2007, Cancer research.

[60]  Piero Carninci,et al.  Noncoding RNA transcription beyond annotated genes. , 2007, Current opinion in genetics & development.

[61]  T. Kouzarides.  Chromatin Modifications and Their Function , 2007, Cell.

[62]  P. Hagerman,et al.  Fragile X-associated tremor/ataxia syndrome—an older face of the fragile X gene , 2007, Nature Clinical Practice Neurology.

[63]  M. Goedert,et al.  A Century of Alzheimer's Disease , 2006, Science.

[64]  G. Tseng,et al.  Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas , 2006, Hepatology.

[65]  T. Ebner,et al.  Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8 , 2006, Nature Genetics.

[66]  J. Mattick,et al.  Non-coding RNA. , 2006, Human molecular genetics.

[67]  S. Salzberg,et al.  The Transcriptional Landscape of the Mammalian Genome , 2005, Science.

[68]  宁北芳,et al.  疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A , 2005 .

[69]  J. Mattick,et al.  Small regulatory RNAs in mammals. , 2005, Human molecular genetics.

[70]  J. Brosius,et al.  Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice , 2004, Behavioural Brain Research.

[71]  P. Hagerman,et al.  FMR1 RNA within the Intranuclear Inclusions of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) , 2004, RNA biology.

[72]  M. Mutsuddi,et al.  The Spinocerebellar Ataxia 8 Noncoding RNA Causes Neurodegeneration and Associates with Staufen in Drosophila , 2004, Current Biology.

[73]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[74]  H. Willard,et al.  Barring gene expression after XIST: maintaining facultative heterochromatin on the inactive X. , 2003, Seminars in cell & developmental biology.

[75]  B. Oostra,et al.  A fragile balance: FMR1 expression levels. , 2003, Human molecular genetics.

[76]  Michael Thomas,et al.  MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer , 2003, Oncogene.

[77]  Jeannie T. Lee,et al.  Xite, X-inactivation intergenic transcription elements that regulate the probability of choice. , 2003, Molecular cell.

[78]  A. Iacoangeli,et al.  Poly(A)-binding protein is associated with neuronal BC1 and BC200 ribonucleoprotein particles. , 2002, Journal of molecular biology.

[79]  P. Hagerman,et al.  A majority of fragile X males with methylated, full mutation alleles have significant levels of FMR1messenger RNA , 2001, Journal of medical genetics.

[80]  Jeannie T. Lee,et al.  Tsix, a gene antisense to Xist at the X-inactivation centre , 1999, Nature Genetics.

[81]  T. Bird,et al.  An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8) , 1999, Nature Genetics.

[82]  J. Brosius,et al.  Primary structure, neural-specific expression, and dendritic location of human BC200 RNA , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[83]  Dominic P. Norris,et al.  The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus , 1992, Cell.

[84]  Carolyn J. Brown,et al.  The human XIST gene: Analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus , 1992, Cell.

[85]  J. Sutcliffe,et al.  Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome , 1991, Cell.