Advertisement

Pseudogene-Expressed RNAs: Emerging Roles in Gene Regulation and Disease

  • Dan Grandér
  • Per JohnssonEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 394)

Abstract

Pseudogenes have for long been considered as non-functional relics littering the human genome. Only now, it is becoming apparent that many pseudogenes are transcribed into long noncoding RNAs, some with proven biological functions. Here, we review the current knowledge of pseudogenes and their widespread functional properties with an emphasis on pseudogenes that have been functionally investigated in greater detail. Pseudogenes are emerging as a novel class of long noncoding RNAs functioning, for example, through microRNA sponging and chromatin remodeling. The examples discussed herein underline that pseudogene-encoded RNAs are important regulatory molecules involved in diseases such as cancer.

Keywords

Noncoding RNAs OCT4 Expression Functional Investigation miRNA Sponge PTEN Promoter 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Research reported in this publication was supported by the Swedish Childhood Cancer Foundation, The Swedish Cancer Society, Radiumhemmets Forskningsfonder, Vetenskapsrådet to Dan Grandér.

References

  1. Ohshima K et al (2003) Whole-genome screening indicates a possible burst of formation of processed pseudogenes and Alu repeats by particular L1 subfamilies in ancestral primates. Genome Biol 4:R74Google Scholar
  2. Pei BK et al (2012) The GENCODE pseudogene resource. Genome Biol 13:R51Google Scholar
  3. Hayashi H et al (2013) The OCT4 pseudogene POU5F1B is amplified and promotes an aggressive phenotype in gastric cancer. Oncogene 34:199–208Google Scholar
  4. Johnsson P et al (2013) A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells. Nat Struct Mol Biol 20:440–446Google Scholar
  5. Alimonti A et al (2010) Subtle variations in Pten dose determine cancer susceptibility. Nat Genet 42:454–458CrossRefPubMedPubMedCentralGoogle Scholar
  6. Baillie JK et al (2011) Somatic retrotransposition alters the genetic landscape of the human brain. Nature 479:534–537CrossRefPubMedPubMedCentralGoogle Scholar
  7. Balasubramanian S et al (2009) Comparative analysis of processed ribosomal protein pseudogenes in four mammalian genomes. Genome Biol 10:R2CrossRefPubMedPubMedCentralGoogle Scholar
  8. Batzer MA, Deininger PL (2002) Alu repeats and human genomic diversity. Nat Rev Genet 3:370–379CrossRefPubMedGoogle Scholar
  9. Beltran M et al (2008) A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. Genes Dev 22:756–769CrossRefPubMedPubMedCentralGoogle Scholar
  10. Brockdorff N et al (1992) The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71:515–526CrossRefPubMedGoogle Scholar
  11. Brown CJ et al (1992) The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71:527–542CrossRefPubMedGoogle Scholar
  12. Brunetti A, Manfioletti G, Chiefari E, Goldfine ID, Foti D (2001) Transcriptional regulation of human insulin receptor gene by the high-mobility group protein HMGI(Y). FASEB J 15:492–500CrossRefPubMedGoogle Scholar
  13. Carninci P et al (2005) The transcriptional landscape of the mammalian genome. Science 309:1559–1563CrossRefPubMedGoogle Scholar
  14. Chan WL, Yang WK, Huang HD, Chang JG (2013) pseudoMap: an innovative and comprehensive resource for identification of siRNA-mediated mechanisms in human transcribed pseudogenes. Database (Oxford) 2013:bat001Google Scholar
  15. Chen J et al (2004) Over 20 % of human transcripts might form sense-antisense pairs. Nucleic Acids Res 32:4812–4820CrossRefPubMedPubMedCentralGoogle Scholar
  16. Chiappetta G et al (1995) The expression of the high mobility group HMGI (Y) proteins correlates with the malignant phenotype of human thyroid neoplasias. Oncogene 10:1307–1314PubMedGoogle Scholar
  17. Chiappetta G et al (1996) High level expression of the HMGI (Y) gene during embryonic development. Oncogene 13:2439–2446PubMedGoogle Scholar
  18. Chiefari E et al (2010) Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes. Nat Commun 1:40CrossRefPubMedGoogle Scholar
  19. Chieffi P et al (2002) HMGA1 and HMGA2 protein expression in mouse spermatogenesis. Oncogene 21:3644–3650CrossRefPubMedGoogle Scholar
  20. Cooke SL et al (2014) Processed pseudogenes acquired somatically during cancer development. Nat Commun 5:3644CrossRefPubMedPubMedCentralGoogle Scholar
  21. Coufal NG et al (2009) L1 retrotransposition in human neural progenitor cells. Nature 460:1127–1131CrossRefPubMedPubMedCentralGoogle Scholar
  22. Dahia PL et al (1998) A highly conserved processed PTEN pseudogene is located on chromosome band 9p21. Oncogene 16:2403–2406CrossRefPubMedGoogle Scholar
  23. Djebali S et al (2012) Landscape of transcription in human cells. Nature 489:101–108CrossRefPubMedPubMedCentralGoogle Scholar
  24. Duret L, Chureau C, Samain S, Weissenbach J, Avner P (2006) The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene. Science 312:1653–1655CrossRefPubMedGoogle Scholar
  25. Engstrom PG et al (2006) Complex Loci in human and mouse genomes. PLoS Genet 2:e47CrossRefPubMedPubMedCentralGoogle Scholar
  26. Esnault C, Maestre J, Heidmann T (2000) Human LINE retrotransposons generate processed pseudogenes. Nat Genet 24:363–367CrossRefPubMedGoogle Scholar
  27. Esposito F et al (2014) HMGA1 pseudogenes as candidate proto-oncogenic competitive endogenous RNAs. Oncotarget 5:8341–8354CrossRefPubMedPubMedCentralGoogle Scholar
  28. Feng Q, Moran JV, Kazazian HH Jr, Boeke JD (1996) Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell 87:905–916CrossRefPubMedGoogle Scholar
  29. Foti D et al (2005) Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. Nat Med 11:765–773CrossRefPubMedGoogle Scholar
  30. Frasca F et al (2006) HMGA1 inhibits the function of p53 family members in thyroid cancer cells. Cancer Res 66:2980–2989CrossRefPubMedGoogle Scholar
  31. Frith MC et al (2006) Pseudo-messenger RNA: phantoms of the transcriptome. PLoS Genet 2:e23CrossRefPubMedPubMedCentralGoogle Scholar
  32. Fusco A, Fedele M (2007) Roles of HMGA proteins in cancer. Nat Rev Cancer 7:899–910CrossRefPubMedGoogle Scholar
  33. Giancotti V et al (1985) Changes in nuclear proteins on transformation of rat epithelial thyroid cells by a murine sarcoma retrovirus. Cancer Res 45:6051–6057PubMedGoogle Scholar
  34. Gong CG, Maquat LE (2011) lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature 470:284–288Google Scholar
  35. Grosschedl R, Giese K, Pagel J (1994) HMG domain proteins: architectural elements in the assembly of nucleoprotein structures. Trends Genet 10:94–100CrossRefPubMedGoogle Scholar
  36. Gupta RA et al (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464:1071–1076CrossRefPubMedPubMedCentralGoogle Scholar
  37. Hacisuleyman E et al (2014) Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre. Nat Struct Mol Biol 21:198–206CrossRefPubMedPubMedCentralGoogle Scholar
  38. Hata K, Sakaki Y (1997) Identification of critical CpG sites for repression of L1 transcription by DNA methylation. Gene 189:227–234CrossRefPubMedGoogle Scholar
  39. Hawkins PG, Morris KV (2010) Transcriptional regulation of Oct4 by a long non-coding RNA antisense to Oct4-pseudogene 5. Transcription 1:165–175CrossRefPubMedPubMedCentralGoogle Scholar
  40. Iskow RC et al (2010) Natural mutagenesis of human genomes by endogenous retrotransposons. Cell 141:1253–1261CrossRefPubMedPubMedCentralGoogle Scholar
  41. Jacq C, Miller JR, Brownlee GG (1977) A pseudogene structure in 5S DNA of Xenopus laevis. Cell 12:109–120CrossRefPubMedGoogle Scholar
  42. Johnsson P, Morris KV, Grander D (2014) Pseudogenes: a novel source of trans-acting antisense RNAs. Methods Mol Biol 1167:213–226CrossRefPubMedGoogle Scholar
  43. Kalyana-Sundaram S et al (2012) Expressed pseudogenes in the transcriptional landscape of human cancers. Cell 149:1622–1634CrossRefPubMedPubMedCentralGoogle Scholar
  44. Kastler S et al (2010) POU5F1P1, a putative cancer susceptibility gene, is overexpressed in prostatic carcinoma. Prostate 70:666–674PubMedGoogle Scholar
  45. Katayama S et al (2005) Antisense transcription in the mammalian transcriptome. Science 309:1564–1566CrossRefPubMedGoogle Scholar
  46. Khoo C, Blanchard RK, Sullivan VK, Cousins RJ (1997) Human cysteine-rich intestinal protein: cDNA cloning and expression of recombinant protein and identification in human peripheral blood mononuclear cells. Protein Expr Purif 9:379–387CrossRefPubMedGoogle Scholar
  47. Kim TK et al (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465:182–187CrossRefPubMedPubMedCentralGoogle Scholar
  48. Korneev SA, Park JH, O’Shea M (1999) Neuronal expression of neural nitric oxide synthase (nNOS) protein is suppressed by an antisense RNA transcribed from an NOS pseudogene. J Neurosci 19:7711–7720PubMedGoogle Scholar
  49. Lander ES et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921CrossRefPubMedGoogle Scholar
  50. Latos PA et al (2012) Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science 338:1469–1472CrossRefPubMedGoogle Scholar
  51. Lee JT, Davidow LS, Warshawsky D (1999) Tsix, a gene antisense to Xist at the X-inactivation centre. Nat Genet 21:400–404CrossRefPubMedGoogle Scholar
  52. Lee E et al (2012) Landscape of somatic retrotransposition in human cancers. Science 337:967–971CrossRefPubMedPubMedCentralGoogle Scholar
  53. Levy S et al (2007) The diploid genome sequence of an individual human. PLoS Biol 5:e254CrossRefPubMedPubMedCentralGoogle Scholar
  54. Liedtke S, Enczmann J, Waclawczyk S, Wernet P, Kogler G (2007) Oct4 and its pseudogenes confuse stem cell research. Cell Stem Cell 1:364–366CrossRefPubMedGoogle Scholar
  55. Liu YJ et al (2009) Comprehensive analysis of the pseudogenes of glycolytic enzymes in vertebrates: the anomalously high number of GAPDH pseudogenes highlights a recent burst of retrotrans-positional activity. BMC Genom 10:480CrossRefGoogle Scholar
  56. Mahmoudi S et al (2009) Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage. Mol Cell 33:462–471CrossRefPubMedGoogle Scholar
  57. Margulies EH et al (2005) Comparative sequencing provides insights about the structure and conservation of marsupial and monotreme genomes. Proc Natl Acad Sci USA 102:3354–3359CrossRefPubMedPubMedCentralGoogle Scholar
  58. Mathias SL, Scott AF, Kazazian HH Jr, Boeke JD, Gabriel A (1991) Reverse transcriptase encoded by a human transposable element. Science 254:1808–1810CrossRefPubMedGoogle Scholar
  59. McClintock B (1950) The origin and behavior of mutable loci in maize. Proc Natl Acad Sci USA 36:344–355CrossRefPubMedPubMedCentralGoogle Scholar
  60. Mestdagh P et al (2010) An integrative genomics screen uncovers ncRNA T-UCR functions in neuroblastoma tumours. Oncogene 29:3583–3592CrossRefPubMedGoogle Scholar
  61. Moran JV et al (1996) High frequency retrotransposition in cultured mammalian cells. Cell 87:917–927CrossRefPubMedGoogle Scholar
  62. Morris KV, Mattick JS (2014) The rise of regulatory RNA. Nat Rev Genet 15:423–437CrossRefPubMedPubMedCentralGoogle Scholar
  63. Muotri AR et al (2010) L1 retrotransposition in neurons is modulated by MeCP2. Nature 468:443–446CrossRefPubMedPubMedCentralGoogle Scholar
  64. Muro EM, Andrade-Navarro MA (2010) Pseudogenes as an alternative source of natural antisense transcripts. Bmc Evol Biol 10:338Google Scholar
  65. Niwa H, Miyazaki J, Smith AG (2000) Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24:372–376CrossRefPubMedGoogle Scholar
  66. Pain D, Chirn GW, Strassel C, Kemp DM (2005) Multiple retropseudogenes from pluripotent cell-specific gene expression indicates a potential signature for novel gene identification. J Biol Chem 280:6265–6268CrossRefPubMedGoogle Scholar
  67. Pegoraro S et al (2013) HMGA1 promotes metastatic processes in basal-like breast cancer regulating EMT and stemness. Oncotarget 4:1293–1308CrossRefPubMedPubMedCentralGoogle Scholar
  68. Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (1996) Requirement for Xist in X chromosome inactivation. Nature 379:131–137CrossRefPubMedGoogle Scholar
  69. Pesce M, Scholer HR (2001) Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells 19:271–278CrossRefPubMedGoogle Scholar
  70. Phokaew C, Kowudtitham S, Subbalekha K, Shuangshoti S, Mutirangura A (2008) LINE-1 methylation patterns of different loci in normal and cancerous cells. Nucleic Acids Res 36:5704–5712CrossRefPubMedPubMedCentralGoogle Scholar
  71. Pierantoni GM et al (2001) High mobility group I (Y) proteins bind HIPK2, a serine-threonine kinase protein which inhibits cell growth. Oncogene 20:6132–6141CrossRefPubMedGoogle Scholar
  72. Pierantoni GM et al (2003) High-mobility group A1 proteins are overexpressed in human leukaemias. Biochem J 372:145–150CrossRefPubMedPubMedCentralGoogle Scholar
  73. Pierantoni GM et al (2007) High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2. J Clin Invest 117:693–702CrossRefPubMedPubMedCentralGoogle Scholar
  74. Poliseno L et al (2010) A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465:1033–1038CrossRefPubMedPubMedCentralGoogle Scholar
  75. Poliseno L et al (2011) Deletion of PTENP1 pseudogene in human melanoma. J Invest Dermatol 131:2497–2500CrossRefPubMedPubMedCentralGoogle Scholar
  76. Puget N et al (2002) Distinct BRCA1 rearrangements involving the BRCA1 pseudogene suggest the existence of a recombination hot spot. Am J Hum Genet 70:858–865CrossRefPubMedPubMedCentralGoogle Scholar
  77. Rapicavoli NA et al (2013) A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics. Elife 2:e00762CrossRefPubMedPubMedCentralGoogle Scholar
  78. Reeves R, Nissen MS (1990) The A.T-DNA-binding domain of mammalian high mobility group I chromosomal proteins. A novel peptide motif for recognizing DNA structure. J Biol Chem 265:8573–8582PubMedGoogle Scholar
  79. Rinn JL et al (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129:1311–1323CrossRefPubMedPubMedCentralGoogle Scholar
  80. Sado T, Wang Z, Sasaki H, Li E (2001) Regulation of imprinted X-chromosome inactivation in mice by Tsix. Development 128:1275–1286PubMedGoogle Scholar
  81. Sleutels F, Zwart R, Barlow DP (2002) The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 415:810–813CrossRefPubMedGoogle Scholar
  82. Solyom S et al (2012) Extensive somatic L1 retrotransposition in colorectal tumors. Genome Res 22:2328–2338CrossRefPubMedPubMedCentralGoogle Scholar
  83. Stoger R et al (1993) Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell 73:61–71CrossRefPubMedGoogle Scholar
  84. Suo G et al (2005) Oct4 pseudogenes are transcribed in cancers. Biochem Biophys Res Commun 337:1047–1051CrossRefPubMedGoogle Scholar
  85. Tai MH et al (2005) Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis 26:495–502CrossRefPubMedGoogle Scholar
  86. Takeda J, Seino S, Bell GI (1992) Human Oct3 gene family: cDNA sequences, alternative splicing, gene organization, chromosomal location, and expression at low levels in adult tissues. Nucleic Acids Res 20:4613–4620CrossRefPubMedPubMedCentralGoogle Scholar
  87. Tam OH et al (2008) Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453:534–538CrossRefPubMedPubMedCentralGoogle Scholar
  88. Taylor SI et al (1992) Mutations in the insulin receptor gene. Endocr Rev 13:566–595CrossRefPubMedGoogle Scholar
  89. Taylor SI, Accili D, Imai Y (1994) Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM? Diabetes 43:735–740CrossRefPubMedGoogle Scholar
  90. Tessari MA et al (2003) Transcriptional activation of the cyclin A gene by the architectural transcription factor HMGA2. Mol Cell Biol 23:9104–9116CrossRefPubMedPubMedCentralGoogle Scholar
  91. Thanos D, Maniatis T (1992) The high mobility group protein HMG I(Y) is required for NF-kappa B-dependent virus induction of the human IFN-beta gene. Cell 71:777–789CrossRefPubMedGoogle Scholar
  92. Wang L et al (2013) Pseudogene OCT4-pg4 functions as a natural micro RNA sponge to regulate OCT4 expression by competing for miR-145 in hepatocellular carcinoma. Carcinogenesis 34:1773–1781CrossRefPubMedGoogle Scholar
  93. Watanabe T et al (2008) Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453:539–543CrossRefPubMedGoogle Scholar
  94. Weil D, Power MA, Webb GC, Li CL (1997) Antisense transcription of a murine FGFR-3 psuedogene during fetal developement. Gene 187:115–122CrossRefPubMedGoogle Scholar
  95. Wutz A et al (1997) Imprinted expression of the Igf2r gene depends on an intronic CpG island. Nature 389:745–749CrossRefPubMedGoogle Scholar
  96. Xu N, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS (2009) MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell 137:647–658CrossRefPubMedGoogle Scholar
  97. Yu W et al (2008) Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451:202–206CrossRefPubMedPubMedCentralGoogle Scholar
  98. Zakut-Houri R et al (1983) A single gene and a pseudogene for the cellular tumour antigen p53. Nature 306:594–597CrossRefPubMedGoogle Scholar
  99. Zangrossi S et al (2007) Oct-4 expression in adult human differentiated cells challenges its role as a pure stem cell marker. Stem Cells 25:1675–1680CrossRefPubMedGoogle Scholar
  100. Zhang ZL, Carriero N, Gerstein M (2004) Comparative analysis of processed pseudogenes in the mouse and human genomes. Trends Genet 20:62–67CrossRefPubMedGoogle Scholar
  101. Zhao S et al (2011) Expression of OCT4 pseudogenes in human tumours: lessons from glioma and breast carcinoma. J Pathol 223:672–682CrossRefPubMedGoogle Scholar
  102. Zhou BS, Beidler DR, Cheng YC (1992) Identification of antisense RNA transcripts from a human DNA topoisomerase I pseudogene. Cancer Res 52:4280–4285PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Oncology-PathologyKarolinska InstitutetSolnaSweden
  2. 2.Ludwig Institute for Cancer ResearchStockholmSweden

Personalised recommendations