Is Autogenous Posttranscriptional Gene Regulation Common?

  • Gary D. StormoEmail author
Part of the RNA Technologies book series (RNATECHN)


The goal of this chapter is to provide evidence and justification for the hypothesis that autogenous, posttranscriptional regulation of gene expression is common. Several examples are known, mostly from bacteria, bacteriophage, and yeast species. Each was identified either by accident or by a concerted effort to understand the regulation of specific genes. The paucity of examples from higher eukaryotes may be due to the difficulty of identifying them using common approaches for uncovering regulatory interactions. An alternative approach is proposed that can fill the gap.


Gene expression regulation Autogenous regulation Posttranscriptional regulation Protein–RNA interactions Feedback regulation 



I thank Drs. Michael White and Basab Roy for comments and suggestions on the manuscript.


  1. Alon U (2007) Network motifs: theory and experimental approaches. Nat Rev Genet 8:450–461CrossRefPubMedGoogle Scholar
  2. Andrake M, Guild N, Hsu T, Gold L, Tuer C et al (1988) DNA polymerase of bacteriophage T4 is an autogenous translational repressor. Proc Natl Acad Sci USA 85:7942–7946CrossRefPubMedGoogle Scholar
  3. Bar-Joseph Z, Gerber GK, Lee TI, Rinaldi NJ, Yoo JY et al (2003) Computational discovery of gene modules and regulatory networks. Nat Biotechnol 21:1337–1342CrossRefPubMedGoogle Scholar
  4. Bateman E (1998) Autoregulation of eukaryotic transcription factors. Prog Nucleic Acid Res Mol Biol 60:133–168CrossRefPubMedGoogle Scholar
  5. Bellur DL, Woodson SA (2009) A minimized rRNA-binding site for ribosomal protein S4 and its implications for 30S assembly. Nucleic Acids Res 37:1886–1896CrossRefPubMedPubMedCentralGoogle Scholar
  6. Betney R, de Silva E, Krishnan J, Stansfield I (2010) Autoregulatory systems controlling translation factor expression: thermostat-like control of translational accuracy. RNA 16:655–663CrossRefPubMedPubMedCentralGoogle Scholar
  7. Breaker RR (2011) Prospects for riboswitch discovery and analysis. Mol Cell 43:867–879CrossRefPubMedPubMedCentralGoogle Scholar
  8. Busser BW, Buly ML, Michelson AM (2008) Toward a systems-level understanding of developmental regulatory networks. Curr Opin Genet Dev 18:521–529CrossRefPubMedPubMedCentralGoogle Scholar
  9. Carthew RW (2006) Gene regulation by microRNAs. Curr Opin Genet Dev 16:203–208CrossRefPubMedGoogle Scholar
  10. Carzaniga T, Deho G, Briani F (2015) RNase III-independent autogenous regulation of Escherichia coli polynucleotide phosphorylase via translational repression. J Bacteriol 197:1931–1938CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chasman D, Roy S (2017) Inference of cell type specific regulatory networks on mammalian lineages. Curr Opin Syst Biol 2:130–139CrossRefPubMedPubMedCentralGoogle Scholar
  12. Cline AL, Bock RM (1966) Translational control of gene expression. Cold Spring Harb Symp Quant Biol 31:321–333CrossRefPubMedGoogle Scholar
  13. Cove DJ (1974) Evolutionary significance of autogenous regulation. Nature 251:256CrossRefPubMedGoogle Scholar
  14. Dassi E (2017) Handshakes and fights: the regulatory interplay of RNA-binding proteins. Front Mol Biosci 4:67CrossRefPubMedPubMedCentralGoogle Scholar
  15. Dassi E, Quattrone A (2012) Tuning the engine: an introduction to resources on post-transcriptional regulation of gene expression. RNA Biol 9:1224–1232CrossRefPubMedPubMedCentralGoogle Scholar
  16. Draper DE (1989) How do proteins recognize specific RNA sites? New clues from autogenously regulated ribosomal proteins. Trends Biochem Sci 14:335–338CrossRefPubMedGoogle Scholar
  17. Elkon R, Agami R (2017) Characterization of noncoding regulatory DNA in the human genome. Nat Biotechnol 35:732–746CrossRefPubMedGoogle Scholar
  18. Fallon AM, Jinks CS, Strycharz GD, Nomura M (1979) Regulation of ribosomal protein synthesis in Escherichia coli by selective mRNA inactivation. Proc Natl Acad Sci USA 76:3411–3415CrossRefPubMedGoogle Scholar
  19. Gilbert WV, Bell TA, Schaening C (2016) Messenger RNA modifications: form, distribution, and function. Science 352:1408–1412CrossRefPubMedPubMedCentralGoogle Scholar
  20. Gold L (1988) Posttranscriptional regulatory mechanisms in Escherichia coli. Annu Rev Biochem 57:199–233CrossRefPubMedGoogle Scholar
  21. Gold L, Polisky B, Uhlenbeck O, Yarus M (1995) Diversity of oligonucleotide functions. Annu Rev Biochem 64:763–797CrossRefPubMedGoogle Scholar
  22. Goldberger RF (1974) Autogenous regulation of gene expression. Science 183:810–816CrossRefPubMedGoogle Scholar
  23. Haraksingh RR, Snyder MP (2013) Impacts of variation in the human genome on gene regulation. J Mol Biol 425:3970–3977CrossRefPubMedGoogle Scholar
  24. Hinnebusch AG, Ivanov IP, Sonenberg N (2016) Translational control by 5’-untranslated regions of eukaryotic mRNAs. Science 352:1413–1416CrossRefPubMedGoogle Scholar
  25. Holt CE, Bullock SL (2009) Subcellular mRNA localization in animal cells and why it matters. Science 326:1212–1216CrossRefPubMedPubMedCentralGoogle Scholar
  26. Huh WK, Falvo JV, Gerke LC, Carroll AS, Howson RW et al (2003) Global analysis of protein localization in budding yeast. Nature 425:686–691CrossRefPubMedGoogle Scholar
  27. Inada T, Nakamura Y (1996) Autogenous control of the suhB gene expression of Escherichia coli. Biochimie 78:209–212CrossRefPubMedGoogle Scholar
  28. Kiser KB, Schmidt MG (1999) Regulation of the Escherichia coli secA gene is mediated by two distinct RNA structural conformations. Curr Microbiol 38:113–121CrossRefPubMedGoogle Scholar
  29. Larsson O, Tian B, Sonenberg N (2013) Toward a genome-wide landscape of translational control. Cold Spring Harb Perspect Biol 5:a012302CrossRefPubMedPubMedCentralGoogle Scholar
  30. Liu Y, Beyer A, Aebersold R (2016) On the dependency of cellular protein levels on mRNA abundance. Cell 165:535–550CrossRefPubMedGoogle Scholar
  31. Lu P, Vogel C, Wang R, Yao X, Marcotte EM (2007) Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation. Nat Biotechnol 25:117–124CrossRefPubMedGoogle Scholar
  32. Lu H, Zhu YF, Xiong J, Wang R, Jia Z (2015) Potential extra-ribosomal functions of ribosomal proteins in Saccharomyces cerevisiae. Microbiol Res 177:28–33CrossRefPubMedGoogle Scholar
  33. Mandal M, Breaker RR (2004) Gene regulation by riboswitches. Nat Rev Mol Cell Biol 5:451–463CrossRefPubMedGoogle Scholar
  34. Martin KC, Ephrussi A (2009) mRNA localization: gene expression in the spatial dimension. Cell 136:719–730CrossRefPubMedPubMedCentralGoogle Scholar
  35. Matia-Gonzalez AM, Laing EE, Gerber AP (2015) Conserved mRNA-binding proteomes in eukaryotic organisms. Nat Struct Mol Biol 22:1027–1033CrossRefPubMedPubMedCentralGoogle Scholar
  36. McCown PJ, Corbino KA, Stav S, Sherlock ME, Breaker RR (2017) Riboswitch diversity and distribution. RNA 23:995–1011CrossRefPubMedPubMedCentralGoogle Scholar
  37. McPheeters DS, Stormo GD, Gold L (1988) Autogenous regulatory site on the bacteriophage T4 gene 32 messenger RNA. J Mol Biol 201:517–535CrossRefPubMedGoogle Scholar
  38. Miranda-Rios J, Navarro M, Soberon M (2001) A conserved RNA structure (thi box) is involved in regulation of thiamin biosynthetic gene expression in bacteria. Proc Natl Acad Sci USA 98:9736–9741CrossRefPubMedGoogle Scholar
  39. Mironov AS, Gusarov I, Rafikov R, Lopez LE, Shatalin K et al (2002) Sensing small molecules by nascent RNA: a mechanism to control transcription in bacteria. Cell 111:747–756CrossRefPubMedGoogle Scholar
  40. Mitchell SF, Jain S, She M, Parker R (2013) Global analysis of yeast mRNPs. Nat Struct Mol Biol 20:127–133CrossRefPubMedGoogle Scholar
  41. Nomura M (2011) Journey of a molecular biologist. Annu Rev Biochem 80:16–40CrossRefPubMedGoogle Scholar
  42. Nomura M, Gourse R, Baughman G (1984) Regulation of the synthesis of ribosomes and ribosomal components. Annu Rev Biochem 53:75–117CrossRefPubMedGoogle Scholar
  43. Pasquinelli AE (2012) MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet 13:271–282CrossRefPubMedGoogle Scholar
  44. Petrov VM, Karam JD (2002) RNA determinants of translational operator recognition by the DNA polymerases of bacteriophages T4 and RB69. Nucleic Acids Res 30:3341–3348CrossRefPubMedPubMedCentralGoogle Scholar
  45. Pinho R, Garcia V, Irimia M, Feldman MW (2014) Stability depends on positive autoregulation in Boolean gene regulatory networks. PLoS Comput Biol 10:e1003916CrossRefPubMedPubMedCentralGoogle Scholar
  46. Ptashne M, Backman K, Humayun MZ, Jeffrey A, Maurer R et al (1976) Autoregulation and function of a repressor in bacteriophage lambda. Science 194:156–161CrossRefPubMedGoogle Scholar
  47. Ptashne M, Jeffrey A, Johnson AD, Maurer R, Meyer BJ et al (1980) How the lambda repressor and cro work. Cell 19:1–11CrossRefPubMedGoogle Scholar
  48. Ptashne M, Johnson AD, Pabo CO (1982) A genetic switch in a bacterial virus. Sci Am 247:128–130, 132, 134–140Google Scholar
  49. Qu H, Fang X (2013) A brief review on the human encyclopedia of DNA elements (ENCODE) project. Genomics Proteomics Bioinformatics 11:135–141CrossRefPubMedPubMedCentralGoogle Scholar
  50. Romby P, Springer M (2003) Bacterial translational control at atomic resolution. Trends Genet 19:155–161CrossRefPubMedGoogle Scholar
  51. Romby P, Moine H, Lesage P, Graffe M, Dondon J et al (1990) The relation between catalytic activity and gene regulation in the case of E. coli threonyl-tRNA synthetase. Biochimie 72:485–494CrossRefPubMedGoogle Scholar
  52. Russel M, Gold L, Morrissett H, O’Farrell PZ (1976) Translational, autogenous regulation of gene 32 expression during bacteriophage T4 infection. J Biol Chem 251:7263–7270PubMedGoogle Scholar
  53. Savageau MA (1975) Significance of autogenously regulated and constitutive synthesis of regulatory proteins in repressible biosynthetic systems. Nature 258:208–214CrossRefPubMedGoogle Scholar
  54. Schlax PJ, Xavier KA, Gluick TC, Draper DE (2001) Translational repression of the Escherichia coli alpha operon mRNA: importance of an mRNA conformational switch and a ternary entrapment complex. J Biol Chem 276:38494–38501CrossRefPubMedGoogle Scholar
  55. Schmidt MO, Brosh RM Jr, Oliver DB (2001) Escherichia coli SecA helicase activity is not required in vivo for efficient protein translocation or autogenous regulation. J Biol Chem 276:37076–37085CrossRefPubMedGoogle Scholar
  56. Schwanhausser B, Busse D, Li N, Dittmar G, Schuchhardt J et al (2011) Global quantification of mammalian gene expression control. Nature 473:337–342CrossRefGoogle Scholar
  57. Shamoo Y, Tam A, Konigsberg WH, Williams KR (1993) Translational repression by the bacteriophage T4 gene 32 protein involves specific recognition of an RNA pseudoknot structure. J Mol Biol 232:89–104CrossRefPubMedGoogle Scholar
  58. Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136:731–745CrossRefPubMedPubMedCentralGoogle Scholar
  59. Springer M, Plumbridge JA, Butler JS, Graffe M, Dondon J et al (1985) Autogenous control of Escherichia coli threonyl-tRNA synthetase expression in vivo. J Mol Biol 185:93–104CrossRefPubMedGoogle Scholar
  60. Stormo GD, Ji Y (2001) Do mRNAs act as direct sensors of small molecules to control their expression? Proc Natl Acad Sci USA 98:9465–9467CrossRefPubMedGoogle Scholar
  61. Torres-Larios A, Dock-Bregeon AC, Romby P, Rees B, Sankaranarayanan R et al (2002) Structural basis of translational control by Escherichia coli threonyl tRNA synthetase. Nat Struct Biol 9:343–347PubMedGoogle Scholar
  62. Tuerk C, Gold L (1990) Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249:505–510CrossRefGoogle Scholar
  63. Tuerk C, Eddy S, Parma D, Gold L (1990) Autogenous translational operator recognized by bacteriophage T4 DNA polymerase. J Mol Biol 213:749–761CrossRefPubMedGoogle Scholar
  64. Uzan M, Miller ES (2010) Post-transcriptional control by bacteriophage T4: mRNA decay and inhibition of translation initiation. Virol J 7:360CrossRefPubMedPubMedCentralGoogle Scholar
  65. Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R (2006) Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 20:515–524CrossRefPubMedGoogle Scholar
  66. Vitreschak AG, Rodionov DA, Mironov AA, Gelfand MS (2004) Riboswitches: the oldest mechanism for the regulation of gene expression? Trends Genet 20:44–50CrossRefPubMedGoogle Scholar
  67. Vogel C, Marcotte EM (2012) Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 13:227–232CrossRefPubMedPubMedCentralGoogle Scholar
  68. Vogel C, Abreu Rde S, Ko D, Le SY, Shapiro BA et al (2010) Sequence signatures and mRNA concentration can explain two-thirds of protein abundance variation in a human cell line. Mol Syst Biol 6:400CrossRefPubMedPubMedCentralGoogle Scholar
  69. von Hippel PH, Kowalczykowski SC, Lonberg N, Newport JW, Paul LS et al (1982) Autoregulation of gene expression: quantitative evaluation of the expression and function of the bacteriophage T4 gene 32 (single-stranded DNA binding) protein system. J Mol Biol 162:795–818CrossRefGoogle Scholar
  70. Wall ME, Hlavacek WS, Savageau MA (2003) Design principles for regulator gene expression in a repressible gene circuit. J Mol Biol 332:861–876CrossRefPubMedGoogle Scholar
  71. Warner JR, McIntosh KB (2009) How common are extraribosomal functions of ribosomal proteins? Mol Cell 34:3–11CrossRefPubMedPubMedCentralGoogle Scholar
  72. Winkler WC, Cohen-Chalamish S, Breaker RR (2002) An mRNA structure that controls gene expression by binding FMN. Proc Natl Acad Sci USA 99:15908–15913CrossRefPubMedGoogle Scholar
  73. Wu H, Jiang L, Zimmermann RA (1994) The binding site for ribosomal protein S8 in 16S rRNA and spc mRNA from Escherichia coli: minimum structural requirements and the effects of single bulged bases on S8-RNA interaction. Nucleic Acids Res 22:1687–1695CrossRefPubMedPubMedCentralGoogle Scholar
  74. Wyrick JJ, Young RA (2002) Deciphering gene expression regulatory networks. Curr Opin Genet Dev 12:130–136CrossRefPubMedGoogle Scholar
  75. Xu X, Ji Y, Stormo GD (2009) Discovering cis-regulatory RNAs in Shewanella genomes by support vector machines. PLoS Comput Biol 5:e1000338CrossRefPubMedPubMedCentralGoogle Scholar
  76. Yan S, Acharya S, Groning S, Grosshans J (2017) Slam protein dictates subcellular localization and translation of its own mRNA. PLoS Biol 15:e2003315CrossRefPubMedPubMedCentralGoogle Scholar
  77. Yao P, Poruri K, Martinis SA, Fox PL (2014) Non-catalytic regulation of gene expression by aminoacyl-tRNA synthetases. Top Curr Chem 344:167–187CrossRefPubMedGoogle Scholar
  78. Yates JL, Arfsten AE, Nomura M (1980) In vitro expression of Escherichia coli ribosomal protein genes: autogenous inhibition of translation. Proc Natl Acad Sci USA 77:1837–1841CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Genetics and Edison Family Center for Genome Sciences and Systems BiologyWashington University School of MedicineSt LouisUSA

Personalised recommendations