Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs

The recent discovery that the human and other mammalian genomes produce thousands of long non-coding RNAs (lncRNAs) raises many fascinating questions. These mRNA-like molecules, which lack significant protein-coding capacity, have been implicated in a wide range of biological functions through diverse and as yet poorly understood molecular mechanisms. Despite some recent insights into how lncRNAs function in such diverse cellular processes as regulation of gene expression and assembly of cellular structures, by and large, the key questions regarding lncRNA mechanisms remain to be answered. In this review, we discuss recent advances in understanding the biology of lncRNAs and propose avenues of investigation that may lead to fundamental new insights into their functions and mechanisms of action. Finally, as numerous lncRNAs are dysregulated in human diseases and disorders, we also discuss potential roles for these molecules in human health.

[1]  J. Mattick.  The Genetic Signatures of Noncoding RNAs , 2009, PLoS genetics.

[2]  J. Rinn,et al.  The transcriptional activity of human Chromosome 22. , 2003, Genes & development.

[3]  Nicholas T. Ingolia,et al.  Ribosome Profiling of Mouse Embryonic Stem Cells Reveals the Complexity and Dynamics of Mammalian Proteomes , 2011, Cell.

[4]  Michael F. Lin,et al.  Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. , 2012, Genome research.

[5]  Carolyn J. Brown,et al.  A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome , 1991, Nature.

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

[7]  P. Fraser,et al.  No-Nonsense Functions for Long Noncoding RNAs , 2011, Cell.

[8]  J. Mattick,et al.  Long non-coding RNAs in nervous system function and disease , 2010, Brain Research.

[9]  T. Derrien,et al.  Long Noncoding RNAs with Enhancer-like Function in Human Cells , 2010, Cell.

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

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

[12]  John N. Hutchinson,et al.  An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. , 2009, Molecular cell.

[13]  M. Todesco,et al.  Target mimicry provides a new mechanism for regulation of microRNA activity , 2007, Nature Genetics.

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

[15]  E. Birney,et al.  Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs , 2002, Nature.

[16]  Jennifer A. Mitchell,et al.  The Air Noncoding RNA Epigenetically Silences Transcription by Targeting G9a to Chromatin , 2008, Science.

[17]  P. Robson,et al.  Conserved long noncoding RNAs transcriptionally regulated by Oct4 and Nanog modulate pluripotency in mouse embryonic stem cells. , 2010, RNA.

[18]  John L Rinn,et al.  RNA traffic control of chromatin complexes. , 2010, Current opinion in genetics & development.

[19]  Shuhan Sun,et al.  Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans , 2011, Hepatology.

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

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

[22]  Michael Q. Zhang,et al.  Regulating Gene Expression through RNA Nuclear Retention , 2005, Cell.

[23]  J. Rinn,et al.  Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells , 2010, Nature Genetics.

[24]  Y. Pekarsky,et al.  The role of microRNA and other non-coding RNA in the pathogenesis of chronic lymphocytic leukemia. , 2007, Best practice & research. Clinical haematology.

[25]  J. Rinn,et al.  Ab initio reconstruction of transcriptomes of pluripotent and lineage committed cells reveals gene structures of thousands of lincRNAs , 2010, Nature biotechnology.

[26]  John S Mattick,et al.  Long noncoding RNAs in cell biology. , 2011, Seminars in cell & developmental biology.

[27]  Hiroyuki Sasaki,et al.  Genomic imprinting in mammals: its life cycle, molecular mechanisms and reprogramming , 2011, Cell Research.

[28]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[29]  F. Zhang,et al.  Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation , 2012, Medical Oncology.

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

[31]  G. Chrousos,et al.  Noncoding RNA Gas5 Is a Growth Arrest– and Starvation-Associated Repressor of the Glucocorticoid Receptor , 2010, Science Signaling.

[32]  J. Gribnau,et al.  Xist regulation and function eXplored , 2011, Human Genetics.

[33]  S. Batalov,et al.  Antisense Transcription in the Mammalian Transcriptome , 2005, Science.

[34]  D. J. Driscoll,et al.  Trimethylation of Histone H3 Lysine 4 is an Epigenetic Mark at Regions Escaping Mammalian X Inactivation , 2007, Epigenetics.

[35]  J. Mattick,et al.  Non‐coding RNAs: regulators of disease , 2010, The Journal of pathology.

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

[37]  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.

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

[39]  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.

[40]  A. Feinberg,et al.  Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA , 2008, Nature.

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

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

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

[44]  Yingying Lian,et al.  Role of human noncoding RNAs in the control of tumorigenesis , 2009, Proceedings of the National Academy of Sciences.

[45]  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.

[46]  Howard Y. Chang,et al.  Genome-wide measurement of RNA secondary structure in yeast , 2010, Nature.

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

[48]  Elphège P. Nora,et al.  Regulation of X-chromosome inactivation by the X-inactivation centre , 2011, Nature Reviews Genetics.

[49]  L. Kemény,et al.  Identification and Characterization of a Novel, Psoriasis Susceptibility-related Noncoding RNA gene, PRINS* , 2005, Journal of Biological Chemistry.

[50]  J. Mattick,et al.  Long non-coding RNAs: insights into functions , 2009, Nature Reviews Genetics.

[51]  D. Bartel,et al.  Conserved Function of lincRNAs in Vertebrate Embryonic Development despite Rapid Sequence Evolution , 2011, Cell.

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

[53]  C. Kanduri,et al.  Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1 , 2010, Development.

[54]  J. Rinn,et al.  Ab initio reconstruction of transcriptomes of pluripotent and lineage committed cells reveals gene structures of thousands of lincRNAs , 2010, Nature Biotechnology.

[55]  Paulo P. Amaral,et al.  The Eukaryotic Genome as an RNA Machine , 2008, Science.

[56]  Christopher P Austin,et al.  The Knockout Mouse Project , 2004, Nature Genetics.

[57]  Howard Y. Chang,et al.  A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression , 2011, Nature.

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

[59]  A. Werner,et al.  What do natural antisense transcripts regulate? , 2009, RNA biology.

[60]  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.

[61]  Brian S. Clark,et al.  The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. , 2006, Genes & development.

[62]  C. H. Neuswanger,et al.  Urology , 1939, The Yale Journal of Biology and Medicine.

[63]  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.

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

[65]  Thomas D. Schmittgen,et al.  Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. , 2007, Cancer cell.

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

[67]  Yusuke Nakamura,et al.  Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction , 2006, Journal of Human Genetics.

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

[69]  James A. Cuff,et al.  A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells , 2006, Cell.

[70]  C. Kanduri,et al.  Epigenetics of imprinted long noncoding RNAs. , 2009, Epigenetics.

[71]  Howard Y. Chang,et al.  Suppression of progenitor differentiation requires the long noncoding RNA ANCR. , 2012, Genes & development.

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

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

[74]  B. Panning.  X inactivation in mouse ES cells: histone modifications and FISH. , 2004, Methods in Enzymology.

[75]  J. Rinn,et al.  Large non-coding RNAs: missing links in cancer? , 2010, Human molecular genetics.

[76]  H. Willard,et al.  X-inactivation profile reveals extensive variability in X-linked gene expression in females , 2005, Nature.

[77]  Sarah Geisler,et al.  Decapping of long noncoding RNAs regulates inducible genes. , 2012, Molecular cell.

[78]  T. Mikkelsen,et al.  Genome-wide maps of chromatin state in pluripotent and lineage-committed cells , 2007, Nature.

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

[80]  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.

[81]  C. Bond,et al.  Paraspeckles: nuclear bodies built on long noncoding RNA , 2009, The Journal of cell biology.

[82]  Patrick Schorderet,et al.  Structural and Functional Differences in the Long Non-Coding RNA Hotair in Mouse and Human , 2011, PLoS genetics.

[83]  D. Spector,et al.  Direct Visualization of the Co-transcriptional Assembly of a Nuclear Body by Noncoding RNAs , 2010, Nature Cell Biology.

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

[85]  Paulo P. Amaral,et al.  MEN epsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. , 2009, Genome research.

[86]  C. Allis,et al.  Methylation of Histone H3 at Lys-9 Is an Early Mark on the X Chromosome during X Inactivation , 2001, Cell.

[87]  C. Ponting,et al.  Evolution and Functions of Long Noncoding RNAs , 2009, Cell.

[88]  W. Reik,et al.  Genomic imprinting: Silence across the border , 2000, Nature.

[89]  M. Dundr,et al.  Nucleation of nuclear bodies by RNA , 2011, Nature Cell Biology.

[90]  Jeannie T. Lee,et al.  The Long Noncoding RNA, Jpx, Is a Molecular Switch for X Chromosome Inactivation , 2010, Cell.

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

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

[93]  X. Chen,et al.  The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells , 2006, Nature Genetics.

[94]  G. Carmichael,et al.  Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA. , 2009, Molecular cell.

[95]  Carolyn J. Brown,et al.  Localization of the X inactivation centre on the human X chromosome in Xq13 , 1991, Nature.

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

[97]  S. Cawley,et al.  Novel RNAs identified from an in-depth analysis of the transcriptome of human chromosomes 21 and 22. , 2004, Genome research.

[98]  E. Dees,et al.  The product of the H19 gene may function as an RNA , 1990, Molecular and cellular biology.

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

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

[101]  M. Barr,et al.  A Morphological Distinction between Neurones of the Male and Female, and the Behaviour of the Nucleolar Satellite during Accelerated Nucleoprotein Synthesis , 1949, Nature.

[102]  Paulo P. Amaral,et al.  RNA regulation of epigenetic processes , 2009, BioEssays : news and reviews in molecular, cellular and developmental biology.

[103]  E. Lander,et al.  The Mammalian Epigenome , 2007, Cell.

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

[105]  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.