Skip to main content

Post-transcriptional Regulation by Proteins and Non-coding RNAs

  • Chapter

Abstract

Posttranscriptional regulation comprises those mechanisms occurring after the initial copy of the DNA sequence is transcribed into an intermediate RNA molecule (i.e., messenger RNA) until such a molecule is used as a template to generate a protein. A subset of these posttranscriptional regulatory mechanisms essentially are destined to process the immature mRNA toward its mature form, conferring the adequate mRNA stability, providing the means for pertinent introns excision, and controlling mRNA turnover rate and quality control check. An additional layer of complexity is added in certain cases, since discrete nucleotide modifications in the mature RNA molecule are added by RNA editing, a process that provides large mature mRNA diversity. Moreover, a number of posttranscriptional regulatory mechanisms occur in a cell- and tissue-specific manner, such as alternative splicing and non-coding RNA-mediated regulation. In this chapter we will briefly summarize current state-of-the-art knowledge of general posttranscriptional mechanisms, while major emphases will be devoted to those tissue-specific posttranscriptional modifications that impact on cardiac development and congenital heart disease.

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

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
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

Learn about institutional subscriptions

References

  1. Lukong KE, Chang KW, Khandjian EW et al (2008) RNA-binding proteins in human genetic disease. Trends Genet 24:416–425

    Article  CAS  PubMed  Google Scholar 

  2. Blech-Hermoni Y, Ladd AN (2013) RNA binding proteins in the regulation of heart development. Int J Biochem Cell Biol 45:2467–2478

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Forget A, Chartrand P (2011) Cotranscriptional assembly of mRNP complexes that determine the cytoplasmic fate of mRNA. Transcription 2:86–90

    Article  PubMed Central  PubMed  Google Scholar 

  4. Fresco LD, Buratowski S (1996) Conditional mutants of the yeast mRNA capping enzyme show that the cap enhances, but is not required for, mRNA splicing. RNA 2:584–596

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Shatkin AJ, Manley JL (2000) The ends of the affair: capping and polyadenylation. Nat Struct Biol 7:838–842

    Article  CAS  PubMed  Google Scholar 

  6. Glover-Cutter K, Kim S, Espinosa J et al (2008) RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes. Nat Struct Mol Biol 15:71–78

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Cowling VH (2009) Regulation of mRNA cap methylation. Biochem J 425:295–302

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. Suh MH, Meyer PA, Gu M et al (2010) A dual interface determines the recognition of RNA polymerase II by RNA capping enzyme. J Biol Chem 285:34027–34038

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Yue Z, Maldonado E, Pillutla R et al (1997) Mammalian capping enzyme complements mutant Saccharomyces cerevisiae lacking mRNA guanylyltransferase and selectively binds the elongating form of RNA polymerase II. Proc Natl Acad Sci U S A 94:12898–12903

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Tsukamoto T, Shibagaki Y, Niikura Y et al (1998) Cloning and characterization of three human cDNAs encoding mRNA (guanine-7-)-methyltransferase, an mRNA cap methylase. Biochem Biophys Res Commun 251:27–34

    Article  CAS  PubMed  Google Scholar 

  11. Yamada-Okabe T, Doi R, Shimmi O et al (1998) Isolation and characterization of a human cDNA for mRNA 5′-capping enzyme. Nucleic Acids Res 26:1700–1706

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Pillutla RC, Shimamoto A, Furuichi Y et al (1998) Human mRNA capping enzyme (RNGTT) and cap methyltransferase (RNMT) map to 6q16 and 18p11.22-p11.23, respectively. Genomics 1998(54):351–353

    Article  Google Scholar 

  13. Ishikawa K, Nagase T, Nakajima D et al (1997) Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro. DNA Res 4:307–313

    Article  CAS  PubMed  Google Scholar 

  14. Konarska MM, Padgett RA, Sharp PA (1984) Recognition of cap structure in splicing in vitro of mRNA precursors. Cell 38:731–736

    Article  CAS  PubMed  Google Scholar 

  15. Spriggs KA, Stoneley M, Bushell M et al (2008) Re-programming of translation following cell stress allows IRES-mediated translation to predominate. Biol Cell 100:27–38

    Article  CAS  PubMed  Google Scholar 

  16. Furuichi Y, LaFiandra A, Shatkin AJ (1977) 5′-Terminal structure and mRNA stability. Nature 266:235–239

    Article  CAS  PubMed  Google Scholar 

  17. Shimotohno K, Kodama Y, Hashimoto J et al (1977) Importance of 5′-terminal blocking structure to stabilize mRNA in eukaryotic protein synthesis. Proc Natl Acad Sci U S A 74:2734–2738

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Murthy KG, Park P, Manley JL (1991) A nuclear micrococcal-sensitive, ATP-dependent exoribonuclease degrades uncapped but not capped RNA substrates. Nucleic Acids Res 19:2685–2692

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Schwer B, Shuman S (1996) Conditional inactivation of mRNA capping enzyme affects yeast pre-mRNA splicing in vivo. RNA 2:574–583

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Schwer B, Mao X, Shuman S (1998) Accelerated mRNA decay in conditional mutants of yeast mRNA capping enzyme. Nucleic Acids Res 26:2050–2057

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Flaherty SM, Fortes P, Izaurralde E et al (1997) Participation of the nuclear cap binding complex in pre-mRNA 3′ processing. Proc Natl Acad Sci U S A 94:11893–11898

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Curinha A, Braz SO, Pereira-Castro I et al (2014) Implications of polyadenylation in health and disease. Nucleus 5:508–519

    Article  PubMed Central  PubMed  Google Scholar 

  23. Tian B, Hu J, Zhang H, Lutz CS (2005) A large-scale analysis of mRNA polyadenylation of human and mouse genes. Nucleic Acids Res 33:201–212

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Pelechano V, Wei W, Steinmetz LM (2013) Extensive transcriptional heterogeneity revealed by isoform profiling. Nature 497:127–131

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Carpenter S, Ricci EP, Mercier BC et al (2014) Post-transcriptional regulation of gene expression in innate immunity. Nat Rev Immunol 14:361–376

    Article  CAS  PubMed  Google Scholar 

  26. Griseri P, Pagès G (2014) Regulation of the mRNA half-life in breast cancer. World J Clin Oncol 5:323–334

    Article  PubMed Central  PubMed  Google Scholar 

  27. Chatterjee S, Pal JK (2009) Role of 5′- and 3′-untranslated regions of mRNAs in human diseases. Biol Cell 101:251–262

    Article  CAS  PubMed  Google Scholar 

  28. Rehfeld A, Plass M, Krogh A et al (2013) Alterations in polyadenylation and its implications for endocrine disease. Front Endocrinol 4:53

    Article  Google Scholar 

  29. Lewis BP, Green RE, Brenner SE (2003) Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc Natl Acad Sci U S A 100:189–192

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Pan Q, Saltzman AL, Kim YK et al (2006) Quantitative microarray profiling provides evidence against widespread coupling of alternative splicing with nonsense-mediated mRNA decay to control gene expression. Genes Dev 20:153–158

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Mendell JT, Sharifi NA, Meyers JL et al (2004) Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nat Genet 36:1073–1078

    Article  CAS  PubMed  Google Scholar 

  32. Wittmann J, Hol EM, Jäck HM (2006) hUPF2 silencing identifies physiologic substrates of mammalian nonsense-mediated mRNA decay. Mol Cell Biol 26:1272–1287

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Ni JZ, Grate L, Donohue JP et al (2007) Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay. Genes Dev 21:708–718

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Chang YF, Imam JS, Wilkinson MF (2007) The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 76:51–74

    Article  CAS  PubMed  Google Scholar 

  35. Maquat LE (2005) Nonsense-mediated mRNA decay in mammals. J Cell Sci 118:1773–1776

    Article  CAS  PubMed  Google Scholar 

  36. Garneau NL, Wilusz J, Wilusz CJ (2007) The highways and byways of mRNA decay. Nat Rev Mol Cell Biol 8:113–126

    Article  CAS  PubMed  Google Scholar 

  37. Ishigaki Y, Li X, Serin G, Maquat LE (2001) Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20. Cell 106:607–617

    Article  CAS  PubMed  Google Scholar 

  38. Lejeune F, Ishigaki Y, Li X, Maquat LE (2002) The exon junction complex is detected on CBP80-bound but not eIF4E-bound mRNA in mammalian cells: dynamics of mRNP remodeling. EMBO J 21:3536–3545

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Lejeune F, Ranganathan AC, Maquat LE (2004) eIF4G is required for the pioneer round of translation in mammalian cells. Nat Struct Mol Biol 11:992–1000

    Article  CAS  PubMed  Google Scholar 

  40. Chiu SY, Lejeune F, Ranganathan AC et al (2004) The pioneer translation initiation complex is functionally distinct from but structurally overlaps with the steady-state translation initiation complex. Genes Dev 18:745–754

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Zhang J, Sun X, Qian Y et al (1998) At least one intron is required for the nonsense-mediated decay of triosephosphate isomerase mRNA: a possible link between nuclear splicing and cytoplasmic translation. Mol Cell Biol 18:5272–5283

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Coller J, Parker R (2004) Eukaryotic mRNA decapping. Annu Rev Biochem 73:861–890

    Article  CAS  PubMed  Google Scholar 

  43. Coller J, Parker R (2005) General translational repression by activators of mRNA decapping. Cell 122:875–886

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Ferraiuolo MA, Basak S, Dostie J et al (2005) A role for the eIF4E-binding protein 4E-T in P-body formation and mRNA decay. Cell Biol 170:913–924

    Article  CAS  Google Scholar 

  45. Braun KA, Young ET (2014) Coupling mRNA synthesis and decay. Mol Cell Biol 34:4078–4087

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  46. Linde L, Kerem B (2008) Introducing sense into nonsense in treatments of human genetic diseases. Trends Genet 24:552–563

    Article  CAS  PubMed  Google Scholar 

  47. Geiger SK, Bar H, Ehlermann P et al (2008) Incomplete nonsense-mediated decay of mutant lamin A/C mRNA provokes dilated cardiomyopathy and ventricular tachycardia. J Mol Med 86:281–289

    Article  CAS  PubMed  Google Scholar 

  48. Gong Q, Zhang L, Vincent GM et al (2007) Nonsense mutations in hERG cause a decrease in mutant mRNA transcripts by nonsense-mediated mRNA decay in human long-QT syndrome. Circulation 116:17–24

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Zarraga IG, Zhang L, Stump MR et al (2011) Nonsense-mediated mRNA decay caused by a frameshift mutation in a large kindred of type 2 long QT syndrome. Heart Rhythm 8:1200–1206

    Article  PubMed Central  PubMed  Google Scholar 

  50. Vignier N, Schlossarek S, Fraysse B et al (2009) Nonsense-mediated mRNA decay and ubiquitin-proteasome system regulate cMyBP-C mutant levels in cardiomyopathic mice. Circ Res 105:239–248

    Article  CAS  PubMed  Google Scholar 

  51. Suzuki S, Nakao A, Sarhat AR et al (2014) A case of pancreatic agenesis and congenital heart defects with a novel GATA6 nonsense mutation: evidence of haploinsufficiency due to nonsense-mediated mRNA decay. Am J Med Genet A 2014(164A):476–479

    Article  CAS  Google Scholar 

  52. Mani A, Radhakrishnan J, Farhi A et al (2005) Syndromic patent ductus arteriosus: evidence for haploinsufficient TFAP2B mutations and identification of a linked sleep disorder. Proc Natl Acad Sci U S A 102:2975–2979

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Chen Z, Eggerman TL, Patterson AP (2007) ApoB mRNA editing is mediated by a coordinated modulation of multiple apoB mRNA editing enzyme components. Am J Physiol Gastrointest Liver Physiol 292:G53–G65

    Article  CAS  PubMed  Google Scholar 

  54. Wedekind JE, Dance GS, Sowden MP et al (2003) Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business. Trends Genet 19:207–216

    Article  CAS  PubMed  Google Scholar 

  55. Galeano F, Tomaselli S, Locatelli F et al (2012) A-to-I RNA editing: the “ADAR” side of human cancer. Semin Cell Dev Biol 23:244–250

    Article  CAS  PubMed  Google Scholar 

  56. Anant S, Henderson J, Mukhopadhyay D et al (2001) Novel role for RNA-binding protein CUGBP2 in mammalian RNA editing. J Biol Chem 276:47338–47351

    Article  CAS  PubMed  Google Scholar 

  57. Blanc V, Davidson NO (2003) C-to-U RNA editing: mechanisms leading to genetic diversity. J Biol Chem 278:1395–1398

    Article  CAS  PubMed  Google Scholar 

  58. Zhang H (2010) The inhibitory effect of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) and its family members on the activity of cellular microRNAs. Prog Mol Subcell Biol 50:71–83

    Article  PubMed  Google Scholar 

  59. Dasgupta T, Ladd AN (2012) The importance of CELF control: molecular and biological roles of the CUG-BP, Elav-like family of RNA-binding proteins. Wiley Interdiscip Rev RNA 3:104–121

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Ohman M (2007) A-to-I editing challenger or ally to the microRNA process. Biochimie 89:1171–1176

    Article  CAS  PubMed  Google Scholar 

  61. Nishikura K (2010) Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem 79:321–349

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Franca R, Spadari S, Maga G (2006) APOBEC deaminases as cellular antiviral factors: a novel natural host defense mechanism. Med Sci Monit 12:RA92–RA98

    CAS  PubMed  Google Scholar 

  63. Vieira VC, Soares MA (2013) The role of cytidine deaminases on innate immune responses against human viral infections. Biomed Res Int 2013:683095

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  64. van den Hoogen BG, van Boheemen S, de Rijck J et al (2014) Excessive production and extreme editing of human metapneumovirus defective interfering RNA is associated with type I IFN induction. J Gen Virol 95:1625–1633

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  65. Sarvestani ST, Tate MD, Moffat JM et al (2014) Inosine-mediated modulation of RNA sensing by Toll-like receptor 7 (TLR7) and TLR8. J Virol 88:799–810

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  66. Clerzius G, Shaw E, Daher A et al (2013) The PKR activator, PACT, becomes a PKR inhibitor during HIV-1 replication. Retrovirology 10:96

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  67. Avesson L, Barry G (2014) The emerging role of RNA and DNA editing in cancer. Biochim Biophys Acta 1845:308–316

    CAS  PubMed  Google Scholar 

  68. Dominissini D, Moshitch-Moshkovitz S, Amariglio N et al (2011) Adenosine-to-inosine RNA editing meets cancer. Carcinogenesis 2011(32):1569–1577

    Article  CAS  Google Scholar 

  69. Li D, Bachinski L, Roberts R (2001) Genomic organization and isoform-specific tissue expression of human NAPOR (CUGBP2) as a candidate gene for familial arrhythmogenic right ventricular dysplasia. Genomics 74:396–401

    Article  CAS  PubMed  Google Scholar 

  70. Lichtner P, Attié-Bitach T, Schuffenhauer S et al (2002) Expression and mutation analysis of Brunol3, a candidate gene for heart and thymus developmental defects associated with partial monosomy 10p. J Mol Med 80:431–442

    Article  CAS  PubMed  Google Scholar 

  71. Wang Z, Burge CB (2008) Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA 14:802–813

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Burge CB, Tuschl T, Sharp PA (1999) Splicing of precursors to mRNAs by the spliceosomes. In: Gesteland RF et al (eds) The RNA world. Cold Spring Harbor Press, Cold Spring Harbor, pp 525–560

    Google Scholar 

  73. Hastings ML, Krainer AR (2001) Pre-mRNA splicing in the new millennium. Curr Opin Cell Biol 13:302–309

    Article  CAS  PubMed  Google Scholar 

  74. Black DL (2003) Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72:291–336

    Article  CAS  PubMed  Google Scholar 

  75. Nissim-Rafinia M, Kerem B (2002) Splicing regulation as a potential genetic modifier. Trends Genet 18:123–127

    Article  CAS  PubMed  Google Scholar 

  76. Han J, Xiong J, Wang D et al (2011) Pre-mRNA splicing: where and when in the nucleus. Trends Cell Biol 21:336–343

    Article  CAS  PubMed  Google Scholar 

  77. Lara-Pezzi E, Gómez-Salinero J, Gatto A, García-Pavía P (2013) The alternative heart: impact of alternative splicing in heart disease. J Cardiovasc Transl Res 6:945–955

    Article  PubMed  Google Scholar 

  78. Ria M, Eriksson P, Boquist S et al (2006) Human genetic evidence that OX40 is implicated in myocardial infarction. Biochem Biophys Res Commun 339:1001–1006

    Article  CAS  PubMed  Google Scholar 

  79. Maatz H, Jens M, Liss M et al (2014) RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing. J Clin Invest 124:3419–3430

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Brauch KM, Karst ML, Herron KJ et al (2009) Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. J Am Coll Cardiol 54:930–941

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Rimessi P, Fabris M, Bovolenta M et al (2010) Antisense modulation of both exonic and intronic splicing motifs induces skipping of a DMD pseudo-exon responsible for x-linked dilated cardiomyopathy. Hum Gene Ther 21:1137–1146

    Article  CAS  PubMed  Google Scholar 

  82. Ruiz-Lozano P, Doevendans P, Brown A et al (1997) Developmental expression of the murine spliceosome-associated protein mSAP49. Dev Dyn 208:482–490

    Article  CAS  PubMed  Google Scholar 

  83. Xu X, Yang D, Ding JH et al (2005) ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle. Cell 120:59–72

    Article  CAS  PubMed  Google Scholar 

  84. Feng Y, Valley MT, Lazar J et al (2009) SRp38 regulates alternative splicing and is required for Ca(2+) handling in the embryonic heart. Dev Cell 16:528–538

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Dally S, Corvazier E, Bredoux R et al (2010) Multiple and diverse coexpression, location, and regulation of additional SERCA2 and SERCA3 isoforms in nonfailing and failing human heart. J Mol Cell Cardiol 48:633–644

    Article  CAS  PubMed  Google Scholar 

  86. Schroeter A, Walzik S, Blechschmidt S et al (2010) Structure and function of splice variants of the cardiac voltage-gated sodium channel Na(v)1.5. J Mol Cell Cardiol 49:16–24

    Article  CAS  PubMed  Google Scholar 

  87. Valadkhan S, Jaladat Y (2010) The spliceosomal proteome: at the heart of the largest cellular ribonucleoprotein machine. Proteomics 10:4128–4141

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Zhang SS, Shaw RM (2013) Multilayered regulation of cardiac ion channels. Biochim Biophys Acta 1833:876–885

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Kjellqvist S, Maleki S, Olsson T et al (2013) A combined proteomic and transcriptomic approach shows diverging molecular mechanisms in thoracic aortic aneurysm development in patients with tricuspid- and bicuspid aortic valve. Mol Cell Proteomics 12:407–425

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Sheng JJ, Jin JP (2014) Gene regulation, alternative splicing, and posttranslational modification of troponin subunits in cardiac development and adaptation: a focused review. Front Physiol 5:165

    Article  PubMed Central  PubMed  Google Scholar 

  91. Biesiadecki BJ, Elder BD, Yu ZB, Jin JP (2002) Cardiac troponin T variants produced by aberrant splicing of multiple exons in animals with high instances of dilated cardiomyopathy. J Biol Chem 277:50275–50285

    Article  CAS  PubMed  Google Scholar 

  92. Biesiadecki BJ, Jin JP (2002) Exon skipping in cardiac troponin T of turkeys with inherited dilated cardiomyopathy. J Biol Chem 277:18459–18468

    Article  CAS  PubMed  Google Scholar 

  93. Wei B, Gao J, Huang XP, Jin JP (2010) Mutual rescues between two dominant negative mutations in cardiac troponin I and cardiac troponin T. J Biol Chem 285:27806–27816

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Hoogaars WM, Barnett P, Rodriguez M et al (2008) TBX3 and its splice variant TBX3 + exon 2a are functionally similar. Pigment Cell Melanoma Res 21:379–387

    Article  CAS  PubMed  Google Scholar 

  95. Georges R, Nemer G, Morin M et al (2008) Distinct expression and function of alternatively spliced Tbx5 isoforms in cell growth and differentiation. Mol Cell Biol 28:4052–4067

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. DeBenedittis P, Jiao K (2011) Alternative splicing of T-box transcription factor genes. Biochem Biophys Res Commun 412:513–517

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Ueyama T, Kasahara H, Ishiwata T et al (2003) Myocardin expression is regulated by Nkx2.5, and its function is required for cardiomyogenesis. Mol Cell Biol 23:9222–9232

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Iida K, Hidaka K, Takeuchi M et al (1999) Expression of MEF2 genes during human cardiac development. Tohoku J Exp Med 187:15–23

    Article  CAS  PubMed  Google Scholar 

  99. Zhu B, Gulick T (2004) Phosphorylation and alternative pre-mRNA splicing converge to regulate myocyte enhancer factor 2C activity. Mol Cell Biol 24:8264–8275

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Schweickert A, Campione M, Steinbeisser H et al (2000) Pitx2 isoforms: involvement of Pitx2c but not Pitx2a or Pitx2b in vertebrate left-right asymmetry. Mech Dev 90:41–51

    Article  CAS  PubMed  Google Scholar 

  101. Yu X, St Amand TR, Wang S et al (2001) Differential expression and functional analysis of Pitx2 isoforms in regulation of heart looping in the chick. Development 128:1005–1013

    CAS  PubMed  Google Scholar 

  102. Lamba P, Hjalt TA, Bernard DJ (2008) Novel forms of Paired-like homeodomain transcription factor 2 (PITX2): generation by alternative translation initiation and mRNA splicing. BMC Mol Biol 9:31

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  103. Mazaud Guittot S, Bouchard MF, Robert-Grenon JP et al (2009) Conserved usage of alternative 5′ untranslated exons of the GATA4 gene. PLoS One 4(12):e8454

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  104. Yehya A, Souki R, Bitar F et al (2006) Differential duplication of an intronic region in the NFATC1 gene in patients with congenital heart disease. Genome 49:1092–1098

    Article  CAS  PubMed  Google Scholar 

  105. Bedard JE, Haaning AM, Ware SM (2011) Identification of a novel ZIC3 isoform and mutation screening in patients with heterotaxy and congenital heart disease. PLoS One 6(8):e23755

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. McCright B, Gao X, Shen L et al (2001) Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. Development 128:491–502

    CAS  PubMed  Google Scholar 

  107. Ricci M, Xu Y, Hammond HL et al (2012) Myocardial alternative RNA splicing and gene expression profiling in early stage hypoplastic left heart syndrome. PLoS One 7(1):e29784

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  108. Paloschi V, Kurtovic S, Folkersen L et al (2011) Impaired splicing of fibronectin is associated with thoracic aortic aneurysm formation in patients with bicuspid aortic valve. Arterioscler Thromb Vasc Biol 31:691–697

    Article  CAS  PubMed  Google Scholar 

  109. Murphy LL, Moon-Grady AJ, Cuneo BF et al (2012) Developmentally regulated SCN5A splice variant potentiates dysfunction of a novel mutation associated with severe fetal arrhythmia. Heart Rhythm 9:590–597

    Article  PubMed Central  PubMed  Google Scholar 

  110. Huang H, Zhang B, Hartenstein PA et al (2005) NXT2 is required for embryonic heart development in zebrafish. BMC Dev Biol 5:7

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  111. Ver Heyen M, Heymans S, Antoons G et al (2001) Replacement of the muscle-specific sarcoplasmic reticulum Ca(2+)-ATPase isoform SERCA2a by the nonmuscle SERCA2b homologue causes mild concentric hypertrophy and impairs contraction-relaxation of the heart. Circ Res 89:838–846

    Article  CAS  PubMed  Google Scholar 

  112. Buyon JP, Tseng CE, Di Donato F et al (1997) Cardiac expression of 52beta, an alternative transcript of the congenital heart block-associated 52-kd SS-A/Ro autoantigen, is maximal during fetal development. Arthritis Rheum 40:655–660

    Article  CAS  PubMed  Google Scholar 

  113. Schonrock N, Harvey RP, Mattick JS (2012) Long noncoding RNAs in cardiac development and pathophysiology. Circ Res 111:1349–1362

    Article  CAS  PubMed  Google Scholar 

  114. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  CAS  PubMed  Google Scholar 

  115. Bauersachs J, Thum T (2011) Biogenesis and regulation of cardiovascular microRNAs. Circ Res 109(3):334–347

    Article  CAS  PubMed  Google Scholar 

  116. Espinoza-Lewis RA, Wang DZ (2012) MicroRNAs in heart development. Curr Top Dev Biol 100:279–317

    Article  CAS  PubMed  Google Scholar 

  117. Chen J, Wang DZ (2012) microRNAs in cardiovascular development. J Mol Cell Cardiol 52:949–957

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  118. Bonet F, Hernandez-Torres F, Franco D (2014) Towards the therapeutic usage of microRNAs in cardiac disease and regeneration. Exp Clin Cardiol 20:720–756

    Google Scholar 

  119. Chinchilla A, Lozano E, Daimi H et al (2011) MicroRNA profiling during mouse ventricular maturation: a role for miR-27 modulating Mef2c expression. Cardiovasc Res 89:98–108

    Article  CAS  PubMed  Google Scholar 

  120. Vacchi-Suzzi C, Hahne F, Scheubel P et al (2013) Heart structure-specific transcriptomic atlas reveals conserved microRNA-mRNA interactions. PLoS One 8:e52442

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  121. Porrello ER, Mahmoud AI, Simpson E et al (2013) Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc Natl Acad Sci U S A 110:187–192

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  122. Hsu J, Hanna P, Van Wagoner DR et al (2012) Whole genome expression differences in human left and right atria ascertained by RNA sequencing. Circ Cardiovasc Genet 5:327–335

    Article  CAS  PubMed  Google Scholar 

  123. Boon RA, Iekushi K, Lechner S et al (2013) MicroRNA-34a regulates cardiac ageing and function. Nature 495:107–110

    Article  CAS  PubMed  Google Scholar 

  124. Dimmeler S, Nicotera P (2013) MicroRNAs in age-related diseases. EMBO Mol Med 5(2):180–190

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. van Rooij E, Sutherland LB, Liu N et al (2006) A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci U S A 103:18255–18260

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  126. Care A, Catalucci D, Felicetti F et al (2007) MicroRNA-133 controls cardiac hypertrophy. Nat Med 13:613–618

    Article  CAS  PubMed  Google Scholar 

  127. Sayed D, Hong C, Chen IY et al (2007) MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res 100:416–424

    Article  CAS  PubMed  Google Scholar 

  128. Fernandes T, Hashimoto NY, Magalhães FC et al (2011) Aerobic exercise training-induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin ii, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin. Hypertension 58:182–189

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  129. Yang KC, Ku YC, Lovett M, Nerbonne JM (2012) Combined deep microRNA and mRNA sequencing identifies protective transcriptomal signature of enhanced PI3Kα signaling in cardiac hypertrophy. J Mol Cell Cardiol 53:101–112

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  130. Reddy S, Zhao M, Hu DQ et al (2012) Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure. Physiol Genomics 44:562–575

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  131. van Rooij E, Sutherland LB, Thatcher JE et al (2008) Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A 105:13027–13032

    Article  PubMed Central  PubMed  Google Scholar 

  132. Drake JI, Bogaard HJ, Mizuno S et al (2011) Molecular signature of a right heart failure program in chronic severe pulmonary hypertension. Am J Respir Cell Mol Biol 45(6):1239–1247

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  133. Yang KC, Yamada KA, Patel AY et al (2014) Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support. Circulation 129:1009–1021

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  134. Lu Y, Zhang Y, Wang N et al (2010) MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation 122:2378–2387

    Article  CAS  PubMed  Google Scholar 

  135. Xiao J, Liang D, Zhang Y et al (2011) MicroRNA expression signature in atrial fibrillation with mitral stenosis. Physiol Genomics 43:655–664

    Article  CAS  PubMed  Google Scholar 

  136. Cooley N, Cowley MJ, Lin RC et al (2012) Influence of atrial fibrillation on microRNA expression profiles in left and right atria from patients with valvular heart disease. Physiol Genomics 44:211–219

    Article  CAS  PubMed  Google Scholar 

  137. Liu Z, Zhou C, Liu Y et al (2012) The expression levels of plasma microRNAs in atrial fibrillation patients. PLoS One 7(9):e44906

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  138. Nishi H, Sakaguchi T, Miyagawa S et al (2013) Impact of microRNA expression in human atrial tissue in patients with atrial fibrillation undergoing cardiac surgery. PLoS One 8:e73397

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  139. Liu G, Huang Y, Lu X et al (2010) Identification and characteristics of microRNAs with altered expression patterns in a rat model of abdominal aortic aneurysms. Tohoku J Exp Med 222:187–193

    Article  CAS  PubMed  Google Scholar 

  140. Zhao Y, Ransom JF, Li A et al (2007) Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129:303–317

    Article  CAS  PubMed  Google Scholar 

  141. Saxena A, Tabin CJ (2010) miRNA-processing enzyme Dicer is necessary for cardiac outflow tract alignment and chamber septation. Proc Natl Acad Sci U S A 107:87–91

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  142. Singh MK, Lu MM, Massera D et al (2011) MicroRNA-processing enzyme Dicer is required in epicardium for coronary vasculature development. J Biol Chem 286:41036–41045

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  143. Fish JE, Santoro MM, Morton SU et al (2008) miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 15:272–284

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  144. Xing HJ, Li YJ, Ma QM et al (2013) Identification of microRNAs present in congenital heart disease associated copy number variants. Eur Rev Med Pharmacol Sci 17(15):2114–2120

    PubMed  Google Scholar 

  145. Li D, Ji L, Liu L et al (2014) Characterization of circulating microRNA expression in patients with a ventricular septal defect. PLoS One 9:e106318

    Article  PubMed Central  PubMed  Google Scholar 

  146. Zhang J, Chang JJ, Xu F et al (2013) MicroRNA deregulation in right ventricular outflow tract myocardium in nonsyndromic tetralogy of fallot. Can J Cardiol 29:1695–1703

    Article  PubMed  Google Scholar 

  147. Lai CT, Ng EK, Chow PC et al (2013) Circulating microRNA expression profile and systemic right ventricular function in adults after atrial switch operation for complete transposition of the great arteries. BMC Cardiovasc Disord 13:73

    Article  PubMed Central  PubMed  Google Scholar 

  148. Yu ZB, Han SP, Bai YF et al (2012) microRNA expression profiling in fetal single ventricle malformation identified by deep sequencing. Int J Mol Med 29:53–60

    CAS  PubMed  Google Scholar 

  149. Nigam V, Sievers HH, Jensen BC et al (2010) Altered microRNAs in bicuspid aortic valve: a comparison between stenotic and insufficient valves. J Heart Valve Dis 19:459–465

    PubMed Central  PubMed  Google Scholar 

  150. de la Morena MT, Eitson JL, Dozmorov IM et al (2013) Signature MicroRNA expression patterns identified in humans with 22q11.2 deletion/DiGeorge syndrome. Clin Immunol 147:11–22

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  151. Zhu S, Cao L, Zhu J et al (2013) Identification of maternal serum microRNAs as novel non-invasive biomarkers for prenatal detection of fetal congenital heart defects. Clin Chim Acta 424:66–72

    Article  CAS  PubMed  Google Scholar 

  152. Yu Z, Han S, Hu P et al (2011) Potential role of maternal serum microRNAs as a biomarker for fetal congenital heart defects. Med Hypotheses 76:424–426

    Article  CAS  PubMed  Google Scholar 

  153. Omran A, Elimam D, Webster KA et al (2013) MicroRNAs: a new piece in the paediatric cardiovascular disease puzzle. Cardiol Young 23:642–655

    Article  PubMed Central  PubMed  Google Scholar 

  154. Ounzain S, Pezzuto I, Micheletti R et al (2014) Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease. J Mol Cell Cardiol 76:55–70

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  155. Scheuermann JC, Boyer LA (2013) Getting to the heart of the matter: long non-coding RNAs in cardiac development and disease. EMBO J 32:1805–1816

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  156. Caley DP, Pink RC, Trujillano D et al (2010) Long noncoding RNAs, chromatin, and development. ScientificWorldJournal 10:90–102

    Article  CAS  PubMed  Google Scholar 

  157. Zhu S, Hu X, Han S et al (2014) Differential expression profile of long non-coding RNAs during differentiation of cardiomyocytes. Int J Med Sci 11:500–507

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  158. Zhu JG, Shen YH, Liu HL et al (2014) Long noncoding RNAs expression profile of the developing mouse heart. J Cell Biochem 115:910–918

    Article  CAS  PubMed  Google Scholar 

  159. Kaushik K, Leonard VE, Kv S et al (2013) Dynamic expression of long non-coding RNAs (lncRNAs) in adult zebrafish. PLoS One 8:e83616

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  160. Zhang L, Hamad EA, Vausort M et al (2015) Identification of candidate long noncoding RNAs associated with left ventricular hypertrophy. Clin Transl Sci 8:100–106

    Article  CAS  PubMed  Google Scholar 

  161. Ounzain S, Micheletti R, Beckmann T et al (2015) Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. Eur Heart J 36:353–368

    Article  PubMed Central  PubMed  Google Scholar 

  162. Liu Y, Li G, Lu H et al (2014) Expression profiling and ontology analysis of long noncoding RNAs in post-ischemic heart and their implied roles in ischemia/reperfusion injury. Gene 543:15–21

    Article  CAS  PubMed  Google Scholar 

  163. Liu J, Wang DZ (2014) An epigenetic “LINK(RNA)” to pathological cardiac hypertrophy. Cell Metab 20:555–557

    Article  PubMed  CAS  Google Scholar 

  164. Han P, Li W, Lin CH et al (2014) A long noncoding RNA protects the heart from pathological hypertrophy. Nature 514:102–106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  165. Song G, Shen Y, Zhu J et al (2013) Integrated analysis of dysregulated lncRNA expression in fetal cardiac tissues with ventricular septal defect. PLoS One 8:e77492

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  166. O’Brien JE Jr, Kibiryeva N, Zhou XG et al (2012) Noncoding RNA expression in myocardium from infants with tetralogy of Fallot. Circ Cardiovasc Genet 5:279–286

    Article  PubMed  CAS  Google Scholar 

  167. Grote P, Wittler L, Hendrix D et al (2013) The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev Cell 24:206–214

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  168. Klattenhoff CA, Scheuermann JC, Surface LE et al (2013) Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell 152:570–583

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  169. Chen LL, Yang L (2015) Regulation of circRNA biogenesis. RNA Biol 12:381–388

    Article  PubMed  Google Scholar 

  170. Lasda E, Parker R (2014) Circular RNAs: diversity of form and function. RNA 20:1829–1842

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  171. Matkovich SJ, Edwards JR, Grossenheider TC et al (2014) Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs. Proc Natl Acad Sci U S A 111(33):12264–12269

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  172. Kalsotra A, Wang K, Li PF et al (2010) MicroRNAs coordinate an alternative splicing network during mouse postnatal heart development. Genes Dev 24:653–658

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  173. Xu J, Hu Z, Xu Z et al (2009) Functional variant in microRNA-196a2 contributes to the susceptibility of congenital heart disease in a Chinese population. Hum Mutat 30:1231–1236

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Diego Franco .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer-Verlag Wien

About this chapter

Cite this chapter

Aranega, A.E., Franco, D. (2016). Post-transcriptional Regulation by Proteins and Non-coding RNAs. In: Rickert-Sperling, S., Kelly, R., Driscoll, D. (eds) Congenital Heart Diseases: The Broken Heart. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1883-2_13

Download citation

Publish with us

Policies and ethics