Skip to main content
SpringerLink
Log in

Diverse Functions and Mechanisms of Mammalian Long Noncoding RNAs

  • Protocol
  • First Online:
Book cover Regulatory Non-Coding RNAs

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1206))

Abstract

Long noncoding RNAs are becoming increasingly appreciated as major players in gene regulation. They have been reported to play diverse roles in many biological processes. Here, we discuss their discovery, features, and known functions in cells. While not comprehensive, this chapter should serve to illustrate the power and promise of studying long noncoding RNAs.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Alexander RP et al (2010) Annotating non-coding regions of the genome. Nat Rev Genet 11:559–571

    Article  PubMed  CAS  Google Scholar 

  2. Brockdorff N et al (1991) Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome. Nature 351:329–331

    Article  PubMed  CAS  Google Scholar 

  3. Brown CJ et al (1991) A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349:38–44

    Article  PubMed  CAS  Google Scholar 

  4. Cabili MN et al (2011) Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 25:1915–1927

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Carninci P et al (2005) The transcriptional landscape of the mammalian genome. Science 309:1559–1563

    Article  PubMed  CAS  Google Scholar 

  6. Guttman M et al (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458:223–227

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. He Y et al (2008) The antisense transcriptomes of human cells. Science 322:1855–1857

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Katayama S et al (2005) Antisense transcription in the mammalian transcriptome. Science 309:1564–1566

    Article  PubMed  Google Scholar 

  9. Khalil AM et al (2009) Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A 106:11667–11672

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Okazaki Y et al (2002) Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 420:563–573

    Article  PubMed  Google Scholar 

  11. Mercer TR et al (2008) Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A 105:716–721

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Chen LL, Carmichael GG (2009) Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA. Mol Cell 35:467–478

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Faghihi MA 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 14:723–730

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Gupta RA et al (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464:1071–1076

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Guttman M et al (2011) lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477:295–300

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Hu W et al (2011) Long noncoding RNA-mediated anti-apoptotic activity in murine erythroid terminal differentiation. Genes Dev 25:2573–2578

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Huarte M et al (2010) A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142:409–419

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Khalil AM et al (2008) A novel RNA transcript with antiapoptotic function is silenced in fragile X syndrome. PLoS One 3:e1486

    Article  PubMed  PubMed Central  Google Scholar 

  19. Loewer S et al (2010) Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet 42:1113–1117

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Sheik Mohamed J et al (2010) Conserved long noncoding RNAs transcriptionally regulated by Oct4 and Nanog modulate pluripotency in mouse embryonic stem cells. RNA 16:324–337

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tsai MC et al (2010) Long noncoding RNA as modular scaffold of histone modification complexes. Science 329:689–693

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Ladd PD et al (2007) An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals. Hum Mol Genet 16:3174–3187

    Article  PubMed  CAS  Google Scholar 

  23. Lee JT, Davidow LS, Warshawsky D (1999) Tsix, a gene antisense to Xist at the X-inactivation centre. Nat Genet 21:400–404

    Article  PubMed  CAS  Google Scholar 

  24. Scheele C et al (2007) The human PINK1 locus is regulated in vivo by a non-coding natural antisense RNA during modulation of mitochondrial function. BMC Genomics 8:74

    Article  PubMed  PubMed Central  Google Scholar 

  25. Khaitan D et al (2011) The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion. Cancer Res 71:3852–3862

    Article  PubMed  CAS  Google Scholar 

  26. Rinn JL et al (2003) The transcriptional activity of human chromosome 22. Genes Dev 17:529–540

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Guttman M et al (2010) Ab initio reconstruction of cell type-specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs. Nat Biotechnol 28:503–510

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Augui S, Nora EP, Heard E (2011) Regulation of X-chromosome inactivation by the X-inactivation centre. Nat Rev Genet 12:429–442

    Article  PubMed  CAS  Google Scholar 

  29. Brown CJ et al (1991) Localization of the X inactivation centre on the human X chromosome in Xq13. Nature 349:82–84

    Article  PubMed  CAS  Google Scholar 

  30. Jeon Y, Lee JT (2011) YY1 tethers Xist RNA to the inactive X nucleation center. Cell 146:119–133

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Zhao J et al (2008) Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322:750–756

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Tian D, Sun S, Lee JT (2010) The long noncoding RNA, Jpx, is a molecular switch for X chromosome inactivation. Cell 143:390–403

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Mohammad F, Mondal T, Kanduri C (2009) Epigenetics of imprinted long noncoding RNAs. Epigenetics 4:277–286

    Article  PubMed  CAS  Google Scholar 

  34. Rousseaux S et al (2005) Establishment of male-specific epigenetic information. Gene 345:139–153

    Article  PubMed  CAS  Google Scholar 

  35. Pandey RR et al (2008) Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol Cell 32:232–246

    Article  PubMed  CAS  Google Scholar 

  36. Sleutels F, Zwart R, Barlow DP (2002) The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 415:810–813

    Article  PubMed  CAS  Google Scholar 

  37. Nagano T et al (2008) The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322:1717–1720

    Article  PubMed  CAS  Google Scholar 

  38. Young TL, Matsuda T, Cepko CL (2005) The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina. Curr Biol 15:501–512

    Article  PubMed  CAS  Google Scholar 

  39. Rinn JL et al (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129:1311–1323

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Chu C et al (2011) Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. Mol Cell 44:667–678

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Favier B, Dolle P (1997) Developmental functions of mammalian Hox genes. Mol Hum Reprod 3:115–131

    Article  PubMed  CAS  Google Scholar 

  42. Schorderet P, Duboule D (2011) Structural and functional differences in the long non-coding RNA hotair in mouse and human. PLoS Genet 7:e1002071

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Lamond AI, Sleeman JE (2003) Nuclear substructure and dynamics. Curr Biol 13:R825–R828

    Article  PubMed  CAS  Google Scholar 

  44. Bond CS, Fox AH (2009) Paraspeckles: nuclear bodies built on long noncoding RNA. J Cell Biol 186:637–644

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  45. Clemson CM et al (2009) An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. Mol Cell 33:717–726

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Mao YS et al (2011) Direct visualization of the co-transcriptional assembly of a nuclear body by noncoding RNAs. Nat Cell Biol 13:95–101

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Shevtsov SP, Dundr M (2011) Nucleation of nuclear bodies by RNA. Nat Cell Biol 13:167–173

    Article  PubMed  CAS  Google Scholar 

  48. Sunwoo H et al (2009) MEN varepsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Res 19:347–359

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Prasanth KV et al (2005) Regulating gene expression through RNA nuclear retention. Cell 123:249–263

    Article  PubMed  CAS  Google Scholar 

  50. David CJ, Manley JL (2010) Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev 24:2343–2364

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Tripathi V et al (2010) The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39:925–938

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Luo JH et al (2006) Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas. Hepatology 44:1012–1024

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Khalil AM, Rinn JL (2011) RNA-protein interactions in human health and disease. Semin Cell Dev Biol 22:359–365

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. Zhao J et al (2010) Genome-wide identification of polycomb-associated RNAs by RIP-seq. Mol Cell 40:939–953

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  55. Feng J et al (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 20:1470–1484

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Mohammad F et al (2010) Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1. Development 137:2493–2499

    Article  PubMed  CAS  Google Scholar 

  57. Bertani S et al (2011) The noncoding RNA Mistral activates Hoxa6 and Hoxa7 expression and stem cell differentiation by recruiting MLL1 to chromatin. Mol Cell 43:1040–1046

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. Dinger ME et al (2008) Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation. Genome Res 18:1433–1445

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  59. Wang KC et al (2011) A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472:120–124

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. Mattick JS et al (2009) RNA regulation of epigenetic processes. Bioessays 31:51–59

    Article  PubMed  CAS  Google Scholar 

  61. Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10:155–159

    Article  PubMed  CAS  Google Scholar 

  62. Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43:904–914

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  63. Taft RJ et al (2010) Non-coding RNAs: regulators of disease. J Pathol 220:126–139

    Article  PubMed  CAS  Google Scholar 

  64. Kogo R et al (2011) Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res 71:6320–6326

    Article  PubMed  CAS  Google Scholar 

  65. Yang Z et al (2011) Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol 18:1243–1250

    Article  PubMed  Google Scholar 

  66. Calin GA et al (2008) MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci U S A 105:5166–5171

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  67. Gottardo F et al (2007) Micro-RNA profiling in kidney and bladder cancers. Urol Oncol 25:387–392

    Article  PubMed  CAS  Google Scholar 

  68. He L et al (2007) A microRNA component of the p53 tumour suppressor network. Nature 447:1130–1134

    Article  PubMed  CAS  Google Scholar 

  69. Hermeking H (2007) p53 enters the microRNA world. Cancer Cell 12:414–418

    Article  PubMed  CAS  Google Scholar 

  70. Huang Q et al (2008) The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol 10:202–210

    Article  PubMed  CAS  Google Scholar 

  71. Hudson TJ (2011) Cancer genome variation in children, adolescents, and young adults. Cancer 117:2262–2267

    Article  PubMed  CAS  Google Scholar 

  72. Huarte M, Rinn JL (2010) Large non-coding RNAs: missing links in cancer? Hum Mol Genet 19:R152–R161

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  73. Niland CN, Merry CR, Khalil AM (2012) Emerging roles for long non-coding RNAs in cancer and neurological disorders. Front Genet 3:25

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  74. Wapinski O, Chang HY (2011) Long noncoding RNAs and human disease. Trends Cell Biol 21:354–361

    Article  PubMed  CAS  Google Scholar 

  75. Perez DS et al (2008) Long, abundantly expressed non-coding transcripts are altered in cancer. Hum Mol Genet 17:642–655

    Article  PubMed  CAS  Google Scholar 

  76. Ji P et al (2003) MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22:8031–8041

    Article  PubMed  Google Scholar 

  77. Kirmizis A et al (2004) Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev 18:1592–1605

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  78. Shi Y et al (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953

    Article  PubMed  CAS  Google Scholar 

  79. Sokol DK et al (2011) Autism, Alzheimer disease, and fragile X: APP, FMRP, and mGluR5 are molecular links. Neurology 76:1344–1352

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  80. Tassone F et al (2000) Fragile X males with unmethylated, full mutation trinucleotide repeat expansions have elevated levels of FMR1 messenger RNA. Am J Med Genet 94:232–236

    Article  PubMed  CAS  Google Scholar 

  81. Tassone F et al (2001) A majority of fragile X males with methylated, full mutation alleles have significant levels of FMR1 messenger RNA. J Med Genet 38:453–456

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  82. Mehler MF, Mattick JS (2006) Non-coding RNAs in the nervous system. J Physiol 575:333–341

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  83. Qureshi IA, Mattick JS, Mehler MF (2010) Long non-coding RNAs in nervous system function and disease. Brain Res 1338:20–35

    Article  PubMed  CAS  Google Scholar 

  84. Verkerk AJ et al (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905–914

    Article  PubMed  CAS  Google Scholar 

  85. Penagarikano O, Mulle JG, Warren ST (2007) The pathophysiology of fragile X syndrome. Annu Rev Genomics Hum Genet 8:109–129

    Article  PubMed  CAS  Google Scholar 

  86. Ballard C et al (2011) Alzheimer’s disease. Lancet 377:1019–1031

    Article  PubMed  Google Scholar 

  87. Mus E, Hof PR, Tiedge H (2007) Dendritic BC200 RNA in aging and in Alzheimer’s disease. Proc Natl Acad Sci U S A 104:10679–10684

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  88. Tiedge H, Chen W, Brosius J (1993) Primary structure, neural-specific expression, and dendritic location of human BC200 RNA. J Neurosci 13:2382–2390

    PubMed  CAS  Google Scholar 

  89. Kremerskothen J et al (1998) Heterodimer SRP9/14 is an integral part of the neural BC200 RNP in primate brain. Neurosci Lett 245:123–126

    Article  PubMed  CAS  Google Scholar 

  90. Muddashetty R et al (2002) Poly(A)-binding protein is associated with neuronal BC1 and BC200 ribonucleoprotein particles. J Mol Biol 321:433–445

    Article  PubMed  CAS  Google Scholar 

  91. Zalfa F 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 280:33403–33410

    Article  PubMed  CAS  Google Scholar 

  92. Vassar R et al (2009) The beta-secretase enzyme BACE in health and Alzheimer’s disease: regulation, cell biology, function, and therapeutic potential. J Neurosci 29:12787–12794

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  93. Cesana M et al (2011) A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147:358–369

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  94. Martianov I et al (2007) Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature 445:666–670

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Callie R. Merry, Courtney Niland & Ahmad M. Khalil Ph.D.

  2. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Callie R. Merry & Ahmad M. Khalil Ph.D.

  3. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106-4973, USA

    Ahmad M. Khalil Ph.D.

Authors
  1. Callie R. Merry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Courtney Niland
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ahmad M. Khalil Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ahmad M. Khalil Ph.D. .

Editor information

Editors and Affiliations

  1. University of Connecticut Health Center, Farmington, Connecticut, USA

    Gordon G. Carmichael

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this protocol

Cite this protocol

Merry, C.R., Niland, C., Khalil, A.M. (2015). Diverse Functions and Mechanisms of Mammalian Long Noncoding RNAs. In: Carmichael, G. (eds) Regulatory Non-Coding RNAs. Methods in Molecular Biology, vol 1206. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1369-5_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-1369-5_1

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-1368-8

  • Online ISBN: 978-1-4939-1369-5

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation