Long noncoding RNAs: an emerging link between gene regulation and nuclear organization.

Mammalian genomes encode thousands of long noncoding RNAs (lncRNAs) that play important roles in diverse biological processes. As a class, lncRNAs are generally enriched in the nucleus and, specifically, within the chromatin-associated fraction. Consistent with their localization, many lncRNAs have been implicated in the regulation of gene expression and in shaping 3D nuclear organization. In this review, we discuss the evidence that many nuclear-retained lncRNAs can interact with various chromatin regulatory proteins and recruit them to specific sites on DNA to regulate gene expression. Furthermore, we discuss the role of specific lncRNAs in shaping nuclear organization and their emerging mechanisms. Based on these examples, we propose a model that explains how lncRNAs may shape aspects of nuclear organization to regulate gene expression.

[1]  Masayuki Yamamoto,et al.  The fission yeast meiotic regulator Mei2p forms a dot structure in the horse-tail nucleus in association with the sme2 locus on chromosome II. , 2003, Molecular biology of the cell.

[2]  Jernej Ule,et al.  CLIP: a method for identifying protein-RNA interaction sites in living cells. , 2005, Methods.

[3]  E. Lander,et al.  The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread Across the X Chromosome , 2013, Science.

[4]  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.

[5]  T. Cech,et al.  Promiscuous RNA binding by Polycomb Repressive Complex 2 , 2013, Nature Structural &Molecular Biology.

[6]  L. Harrington Telomerase primer specificity and chromosome healing , 1991, Nature.

[7]  T. Magnuson,et al.  The Polycomb Group Protein EED Is Dispensable for the Initiation of Random X-Chromosome Inactivation , 2006, PLoS genetics.

[8]  Dmitri A. Nusinow,et al.  Xist RNA and the mechanism of X chromosome inactivation. , 2002, Annual review of genetics.

[9]  T. Jenuwein,et al.  Recruitment of PRC1 function at the initiation of X inactivation independent of PRC2 and silencing , 2006, The EMBO journal.

[10]  A. Tanay,et al.  Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome , 2012, Cell.

[11]  M. Rosenfeld,et al.  LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs , 2013, Nature.

[12]  David R. Kelley,et al.  Long noncoding RNAs regulate adipogenesis , 2013, Proceedings of the National Academy of Sciences.

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

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

[15]  R. Brimacombe,et al.  [19] Intra-RNA and RNA—protein cross-linking techniques in Escherichia coli ribosomes , 1988 .

[16]  R. Jaenisch,et al.  Expression of Xist RNA is sufficient to initiate macrochromatin body formation , 2001, Chromosoma.

[17]  E. Heard,et al.  A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. , 2006, Genes & development.

[18]  M. Guttman,et al.  Methods for comprehensive experimental identification of RNA-protein interactions , 2014, Genome Biology.

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

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

[21]  David G. Knowles,et al.  The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression , 2012, Genome research.

[22]  Aristotelis Tsirigos,et al.  Genome-wide Mapping and Characterization of Notch-Regulated Long Noncoding RNAs in Acute Leukemia , 2014, Cell.

[23]  R. Jaenisch,et al.  A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. , 2000, Molecular cell.

[24]  M. Egholm,et al.  PNA interference mapping demonstrates functional domains in the noncoding RNA Xist , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Sheldon Penman,et al.  Message and non-message sequences adjacent to poly(A) in steady state heterogeneous nuclear RNA of HeLa cells , 1976, Cell.

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

[27]  Benjamin Leblanc,et al.  Polycomb-Dependent Regulatory Contacts between Distant Hox Loci in Drosophila , 2011, Cell.

[28]  D. Reinberg,et al.  Interactions between JARID2 and noncoding RNAs regulate PRC2 recruitment to chromatin. , 2014, Molecular cell.

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

[30]  D. Reinberg,et al.  PRC2 binds to active promoters and contacts nascent RNAs in embryonic stem cells , 2013, Nature Structural &Molecular Biology.

[31]  D. Dorsett,et al.  Cohesin and Polycomb Proteins Functionally Interact to Control Transcription at Silenced and Active Genes , 2013, PLoS genetics.

[32]  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.

[33]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in X Inactivation , 2003, Science.

[34]  T. Misteli The concept of self-organization in cellular architecture , 2001, The Journal of cell biology.

[35]  N. Brockdorff Noncoding RNA and Polycomb recruitment. , 2013, RNA.

[36]  T. Cremer,et al.  Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions , 2007, Nature Reviews Genetics.

[37]  Jan H Bergmann,et al.  Long non-coding RNAs: modulators of nuclear structure and function. , 2014, Current opinion in cell biology.

[38]  E. Wherry Faculty Opinions recommendation of Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. , 2009 .

[39]  Justin Demmerle,et al.  Spatial separation of Xist RNA and polycomb proteins revealed by superresolution microscopy , 2014, Proceedings of the National Academy of Sciences.

[40]  I. Grummt,et al.  The epigenetics of rRNA genes: from molecular to chromosome biology. , 2008, Annual review of cell and developmental biology.

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

[42]  Howard Y. Chang,et al.  Revealing long noncoding RNA architecture and functions using domain-specific chromatin isolation by RNA purification , 2014, Nature Biotechnology.

[43]  B. Ren,et al.  Genome organization and long-range regulation of gene expression by enhancers. , 2013, Current opinion in cell biology.

[44]  K. Helin,et al.  Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. , 2008, Genes & development.

[45]  R. Flavell,et al.  Interchromosomal associations between alternatively expressed loci , 2005, Nature.

[46]  David L. Spector,et al.  Nuclear speckles: a model for nuclear organelles , 2003, Nature Reviews Molecular Cell Biology.

[47]  Giacomo Cavalli,et al.  Polycomb silencing: from linear chromatin domains to 3D chromosome folding. , 2014, Current opinion in genetics & development.

[48]  N. Niikawa,et al.  Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air. , 2005, Human molecular genetics.

[49]  Xuetao Cao,et al.  The STAT3-Binding Long Noncoding RNA lnc-DC Controls Human Dendritic Cell Differentiation , 2014, Science.

[50]  S. Elledge,et al.  Chromatin proteins captured by ChIP–mass spectrometry are linked to dosage compensation in Drosophila , 2013, Nature Structural &Molecular Biology.

[51]  N. Brockdorff,et al.  Mitotically Stable Association of Polycomb Group Proteins Eed and Enx1 with the Inactive X Chromosome in Trophoblast Stem Cells , 2002, Current Biology.

[52]  A. Ashworth,et al.  Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome , 1991, Nature.

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

[54]  C. Glass,et al.  Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation , 2013, Nature.

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

[56]  Matteo Pellegrini,et al.  Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization. , 2013, Cell stem cell.

[57]  Adam Williams,et al.  Interchromosomal association and gene regulation in trans. , 2010, Trends in genetics : TIG.

[58]  R. Perry,et al.  Synthesis and turnover of nuclear and cytoplasmic polyadenylic acid in mouse L cells. , 1974, Journal of molecular biology.

[59]  Chris Anderson,et al.  Beyond the Sequence , 2015 .

[60]  Wange Lu,et al.  Klf4 organizes long-range chromosomal interactions with the oct4 locus in reprogramming and pluripotency. , 2013, Cell stem cell.

[61]  Tom Misteli,et al.  Functional implications of genome topology , 2013, Nature Structural &Molecular Biology.

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

[63]  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.

[64]  D. Reinberg,et al.  Jarid2 Is Implicated in the Initial Xist-Induced Targeting of PRC2 to the Inactive X Chromosome. , 2014, Molecular cell.

[65]  I. Grummt,et al.  Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. , 2010, Genes & development.

[66]  Masayuki Yamamoto,et al.  Meiotic long non-coding meiRNA accumulates as a dot at its genetic locus facilitated by Mmi1 and plays as a decoy to lure Mmi1 , 2014, Open Biology.

[67]  R. Shiekhattar,et al.  Long Noncoding RNAs Usher In a New Era in the Biology of Enhancers , 2013, Cell.

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

[69]  Giacomo Cavalli,et al.  Polycomb: a paradigm for genome organization from one to three dimensions. , 2012, Current opinion in cell biology.

[70]  R. Shiekhattar,et al.  Activating RNAs associate with Mediator to enhance chromatin architecture and transcription , 2013, Nature.

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

[72]  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.

[73]  J. Rinn,et al.  Modular regulatory principles of large non-coding RNAs , 2012, Nature.

[74]  Jennifer E. Phillips-Cremins,et al.  Architectural Protein Subclasses Shape 3D Organization of Genomes during Lineage Commitment , 2013, Cell.

[75]  Michael Y Tolstorukov,et al.  The CLAMP protein links the MSL complex to the X chromosome during Drosophila dosage compensation. , 2013, Genes & development.

[76]  J. Dekker,et al.  The hierarchy of the 3D genome. , 2013, Molecular cell.

[77]  Guramrit Singh,et al.  RIPiT-Seq: a high-throughput approach for footprinting RNA:protein complexes. , 2014, Methods.

[78]  Wei Li,et al.  Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming. , 2013, Cell stem cell.

[79]  W. V. van IJcken,et al.  The inactive X chromosome adopts a unique three-dimensional conformation that is dependent on Xist RNA. , 2011, Genes & development.

[80]  Robert B Darnell,et al.  HITS‐CLIP: panoramic views of protein–RNA regulation in living cells , 2010, Wiley interdisciplinary reviews. RNA.

[81]  J. Mcneil,et al.  XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure , 1996, The Journal of cell biology.

[82]  Michael Morse,et al.  Multiple knockout mouse models reveal lincRNAs are required for life and brain development , 2013, eLife.

[83]  N. Brockdorff,et al.  The matrix protein hnRNP U is required for chromosomal localization of Xist RNA. , 2010, Developmental cell.

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

[85]  Vincent L. Butty,et al.  Braveheart, a Long Noncoding RNA Required for Cardiovascular Lineage Commitment , 2013, Cell.

[86]  J. Ule,et al.  CLIP: construction of cDNA libraries for high-throughput sequencing from RNAs cross-linked to proteins in vivo. , 2009, Methods.

[87]  T. Misteli Beyond the Sequence: Cellular Organization of Genome Function , 2011 .

[88]  M. Dundr,et al.  De Novo Formation of a Subnuclear Body , 2008, Science.

[89]  Jeannie T. Lee,et al.  Regulatory interactions between RNA and polycomb repressive complex 2. , 2014, Molecular cell.

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

[91]  Brad A Chapman,et al.  The genomic binding sites of a noncoding RNA , 2011, Proceedings of the National Academy of Sciences.

[92]  中山 幸輝 A long noncoding RNA protects the heart from pathological hypertrophy , 2015 .

[93]  T. Deerinck,et al.  In vivo analysis of the stability and transport of nuclear poly(A)+ RNA , 1994, The Journal of cell biology.

[94]  J. Steitz,et al.  Evidence for reassociation of RNA-binding proteins after cell lysis: implications for the interpretation of immunoprecipitation analyses. , 2004, RNA.

[95]  Tom Misteli,et al.  Biogenesis of nuclear bodies. , 2010, Cold Spring Harbor perspectives in biology.

[96]  J. Nickerson,et al.  Chromatin architecture and nuclear RNA. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[97]  A. Rao,et al.  The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation , 2007, Nature.

[98]  Howard Y. Chang,et al.  Essential role of lncRNA binding for WDR5 maintenance of active chromatin and embryonic stem cell pluripotency , 2014, eLife.

[99]  Rudolf Jaenisch,et al.  Chromosomal silencing and localization are mediated by different domains of Xist RNA , 2002, Nature Genetics.

[100]  D. Reinberg,et al.  The Polycomb complex PRC2 and its mark in life , 2011, Nature.

[101]  Jennifer A. Mitchell,et al.  Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells , 2010, Nature Genetics.

[102]  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.

[103]  Tom Misteli,et al.  Concepts in nuclear architecture , 2005, BioEssays : news and reviews in molecular, cellular and developmental biology.

[104]  R. Jaenisch,et al.  Long-range cis effects of ectopic X-inactivation centres on a mouse autosome , 1997, Nature.

[105]  S. Rastan,et al.  Requirement for Xist in X chromosome inactivation , 1996, Nature.

[106]  D. Spector,et al.  The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. , 2013, Cancer research.

[107]  D. S. Gross,et al.  Chromatin , 2020, Definitions.

[108]  C. Glass,et al.  Enhancer RNAs and regulated transcriptional programs. , 2014, Trends in biochemical sciences.

[109]  M. Kuroda,et al.  Are we there yet? Initial targeting of the Male-Specific Lethal and Polycomb group chromatin complexes in Drosophila , 2014, Open Biology.

[110]  E. Lundberg,et al.  A global view of protein expression in human cells, tissues, and organs , 2009, Molecular systems biology.

[111]  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.

[112]  Bin Zhang,et al.  Biogenesis and function of nuclear bodies. , 2011, Trends in genetics : TIG.

[113]  R. Brimacombe,et al.  Intra-RNA and RNA-protein cross-linking techniques in Escherichia coli ribosomes. , 1988, Methods in enzymology.

[114]  David R. Kelley,et al.  Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre , 2014, Nature Structural &Molecular Biology.

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

[116]  Cameron S. Osborne,et al.  Myc Dynamically and Preferentially Relocates to a Transcription Factory Occupied by Igh , 2007, PLoS biology.

[117]  G. Brawerman,et al.  Metabolism of the polyadenylate sequence of nuclear RNA and messenger RNA in mammalian cells , 1975, Cell.

[118]  J. Lewis,et al.  Like attracts like: getting RNA processing together in the nucleus. , 2000, Science.

[119]  Daniel R. Caffrey,et al.  A Long Noncoding RNA Mediates Both Activation and Repression of Immune Response Genes , 2013, Science.

[120]  M. Atchison Function of YY1 in Long-Distance DNA Interactions , 2014, Front. Immunol..

[121]  R. Young,et al.  SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. , 2009, Genes & development.

[122]  Matthias Mann,et al.  Paraspeckles A Novel Nuclear Domain , 2002, Current Biology.

[123]  T. Magnuson,et al.  Imprinted X inactivation maintained by a mouse Polycomb group gene , 2001, Nature Genetics.

[124]  Z. Xue,et al.  The nucleolus: an organelle formed by the act of building a ribosome. , 1995, Current opinion in cell biology.

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

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

[127]  N. Brockdorff,et al.  Establishment of histone h3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes. , 2003, Developmental cell.

[128]  T. Cheutin,et al.  Identification of regulators of the three-dimensional polycomb organization by a microscopy-based genome-wide RNAi screen. , 2014, Molecular cell.

[129]  D. Barlow,et al.  Imprinted silencing is extended over broad chromosomal domains in mouse extra-embryonic lineages , 2013, Current opinion in cell biology.

[130]  J. Nickerson,et al.  Core filaments of the nuclear matrix , 1990, The Journal of cell biology.

[131]  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.

[132]  A. Rump,et al.  A misplaced lncRNA causes brachydactyly in humans. , 2012, The Journal of clinical investigation.

[133]  Jeannie T. Lee,et al.  Locked nucleic acids (LNAs) reveal sequence requirements and kinetics of Xist RNA localization to the X chromosome , 2010, Proceedings of the National Academy of Sciences.

[134]  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.

[135]  D. Duboule,et al.  Temporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci , 2014, eLife.

[136]  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.

[137]  Howard Y. Chang,et al.  Genome regulation by long noncoding RNAs. , 2012, Annual review of biochemistry.

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