Heritable Change Caused by Transient Transcription Errors

English version České info

Transmission of cellular identity relies on the faithful transfer of information from the mother to the daughter cell. This process includes accurate replication of the DNA, but also the correct propagation of regulatory programs responsible for cellular identity. Errors in DNA replication (mutations) and protein conformation (prions) can trigger stable phenotypic changes and cause human disease, yet the ability of transient transcriptional errors to produce heritable phenotypic change (‘epimutations’) remains an open question. Here, we demonstrate that transcriptional errors made specifically in the mRNA encoding a transcription factor can promote heritable phenotypic change by reprogramming a transcriptional network, without altering DNA. We have harnessed the classical bistable switch in the lac operon, a memory-module, to capture the consequences of transient transcription errors in living Escherichia coli cells. We engineered an error-prone transcription sequence (A₉ run) in the gene encoding the lac repressor and show that this ‘slippery’ sequence directly increases epigenetic switching, not mutation in the cell population. Therefore, one altered transcript within a multi-generational series of many error-free transcripts can cause long-term phenotypic consequences. Thus, like DNA mutations, transcriptional epimutations can instigate heritable changes that increase phenotypic diversity, which drives both evolution and disease.

Vyšlo v časopise: Heritable Change Caused by Transient Transcription Errors. PLoS Genet 9(6): e32767. doi:10.1371/journal.pgen.1003595
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003595

Souhrn

Zdroje

1. RandoOJ, VerstrepenKJ (2007) Timescales of genetic and epigenetic inheritance. Cell 128: 655–668 doi:10.1016/j.cell.2007.01.023

2. DrummondDA, WilkeCO (2009) The evolutionary consequences of erroneous protein synthesis. Nat Rev Genet 10: 715–724 doi:10.1038/nrg2662

3. SatoryD, GordonAJ, HallidayJA, HermanC (2011) Epigenetic switches: can infidelity govern fate in microbes? Curr Opin Microbiol 14: 212–217 doi:10.1016/j.mib.2010.12.004

4. MonodJ, JacobF (1961) General conclusions: teleonomic mechanisms in cellular metabolism, growth, and differentiation. Cold Spring Harb Symp Quant Biol 26: 389–401.

5. PasqueV, JullienJ, MiyamotoK, Halley-StottRP, GurdonJB (2011) Epigenetic factors influencing resistance to nuclear reprogramming. Trends Genet 27: 516–525 doi:10.1016/j.tig.2011.08.002

6. TakahashiK, TanabeK, OhnukiM, NaritaM, IchisakaT, et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861–872 doi:10.1016/j.cell.2007.11.019

7. DubnauD, LosickR (2006) Bistability in bacteria. Mol Microbiol 61: 564–572 doi:10.1111/j.1365-2958.2006.05249.x

8. NovickA, WeinerM (1957) Enzyme induction as an all-or-none phenomenon. Proc Natl Acad Sci USA 43: 553–566.

9. Ptashne M (2004) A genetic switch. New York: Cold Spring Harbor Laboratory Press. 164 p.

10. GardnerTS, CantorCR, CollinsJJ (2000) Construction of a genetic toggle switch in Escherichia coli. Nature 403: 339–342 doi:10.1038/35002131

11. KalmarT, LimC, HaywardP, Muñoz-DescalzoS, NicholsJ, et al. (2009) Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biol 7: e1000149 doi:10.1371/journal.pbio.1000149.g008

12. WykoffDD, RizviAH, RaserJM, MargolinB, O'SheaEK (2007) Positive feedback regulates switching of phosphate transporters in S. cerevisiae. Mol Cell 27: 1005–1013 doi:10.1016/j.molcel.2007.07.022

13. FerrellJE, MachlederEM (1998) The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes. Science 280: 895–898.

14. WeinbergerLS, DarRD, SimpsonML (2008) Transient-mediated fate determination in a transcriptional circuit of HIV. Nat Genet 40: 466–470 doi:10.1038/ng.116

15. YaoG, LeeTJ, MoriS, NevinsJR, YouL (2008) A bistable Rb–E2F switch underlies the restriction point. Nat Cell Biol 10: 476–482 doi:10.1038/ncb1711

16. KaufmannBB, YangQ, MettetalJT, van OudenaardenA (2007) Heritable stochastic switching revealed by single-cell genealogy. PLoS Biol 5: e239 doi:10.1371/journal.pbio.0050239

17. ChoiPJ, CaiL, FriedaK, XieXS (2008) A stochastic single-molecule event triggers phenotype switching of a bacterial cell. Science 322: 442–446 doi:10.1126/science.1161427

18. GordonAJE, HallidayJA, BlankschienMD, BurnsPA, YatagaiF, et al. (2009) Transcriptional infidelity promotes heritable phenotypic change in a bistable gene network. PLoS Biol 7: e44 doi:10.1371/journal.pbio.1000044.st002

19. StepanovaE, LeeJ, OzerovaM, SemenovaE, DatsenkoK, et al. (2007) Analysis of promoter targets for Escherichia coli transcription elongation factor GreA in vivo and in vitro. J Bacteriol 189: 8772–8785 doi:10.1128/JB.00911-07

20. KaplanC (2009) Alternate explanation for observed epigenetic behavior? PLoS Biol 7: e44 Available: http://www.plosbiology.org/annotation/listThread.action?root=22157.

21. GordonAJE (2009) Pregnant pauses? PLoS Biol 7: e44 Available: http://www.plosbiology.org/annotation/listThread.action?root=9457.

22. OzbudakEM, ThattaiM, LimHN, ShraimanBI, Van OudenaardenA (2004) Multistability in the lactose utilization network of Escherichia coli. Nature 427: 737–740 doi:10.1038/nature02298

23. ChamberlinM, BergP (1962) Deoxyribonucleic acid-directed synthesis of ribonucleic acid by an enzyme from Escherichia coli. Proc Natl Acad Sci USA 48: 81.

24. WagnerLA, WeissRB, DriscollR, DunnDS, GestelandRF (1990) Transcriptional slippage occurs during elongation at runs of adenine or thymine in Escherichia coli. Nucleic Acids Research 18: 3529–3535.

25. StrathernJN, JinDJ, CourtDL, KashlevM (2012) Isolation and characterization of transcription fidelity mutants. Biochim Biophys Acta 1819: 694–699 doi:10.1016/j.bbagrm.2012.02.005

26. StrathernJ, MalagonF, IrvinJ, GotteD, ShaferB, et al. (2013) The fidelity of transcription: RPB1 (RPO21) mutations that increase transcriptional slippage in S. cerevisiae. J Biol Chem 288: 2689–2699 doi:10.1074/jbc.M112.429506

27. LarsenB, WillsNM, NelsonC, AtkinsJF, GestelandRF (2000) Nonlinearity in genetic decoding: homologous DNA replicase genes use alternatives of transcriptional slippage or translational frameshifting. Proc Natl Acad Sci USA 97: 1683–1688.

28. ZhouYN, LubkowskaL, HuiM, CourtC, ChenS, et al. (2013) Isolation and characterization of RNA Polymerase rpoB mutations that alter transcription slippage during elongation in Escherichia coli. J Biol Chem 288: 2700–2710 doi:10.1074/jbc.M112.429464

29. LintonMF, PierottiV, YoungSG (1992) Reading-frame restoration with an apolipoprotein B gene frameshift mutation. Proc Natl Acad Sci USA 89: 11431–11435.

30. LintonMF, RaabeM, PierottiV, YoungSG (1997) Reading-frame restoration by transcriptional slippage at long stretches of adenine residues in mammalian cells. J Biol Chem 272: 14127–14132.

31. YoungM, InabaH, HoyerLW, HiguchiM, KazazianHH, et al. (1997) Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene. Am J Hum Genet 60: 565–573.

32. NudlerE, MustaevA, LukhtanovE, GoldfarbA (1997) The RNA-DNA hybrid maintains the register of transcription by preventing backtracking of RNA polymerase. Cell 89: 33–41.

33. Miller JH (1992) A short course in bacterial genetics. New York: Cold Spring Harbor Laboratory Press. 456 p.

34. SteegeDA (1977) 5′-Terminal nucleotide sequence of Escherichia coli lactose repressor mRNA: features of translational initiation and reinitiation sites. Proc Natl Acad Sci USA 74: 4163–4167.

35. GoldmanSR, EbrightRH, NickelsBE (2009) Direct detection of abortive RNA transcripts in vivo. Science 324: 927–928 doi:10.1126/science.1169237

36. HuhD, PaulssonJ (2010) Non-genetic heterogeneity from stochastic partitioning at cell division. Nat Genet 43: 95–100 doi:10.1038/ng.729

37. ErieDA, HajiseyedjavadiO, YoungMC, Hippel vonPH (1993) Multiple RNA polymerase conformations and GreA: control of the fidelity of transcription. Science 262: 867–873.

38. ShaevitzJW, AbbondanzieriEA, LandickR, BlockSM (2003) Backtracking by single RNA polymerase molecules observed at near-base-pair resolution. Nature 426: 684–687 doi:10.1038/nature02191

39. ZenkinN, YuzenkovaY, SeverinovK (2006) Transcript-assisted transcriptional proofreading. Science 313: 518–520 doi:10.1126/science.1127422

40. KennellD, RiezmanH (1977) Transcription and translation initiation frequencies of the Escherichia coli lac operon. J Mol Biol 114: 1–21.

41. CaiL, FriedmanN, XieXS (2006) Stochastic protein expression in individual cells at the single molecule level. Nature 440: 358–362 doi:10.1038/nature04599

42. Müller-HillB, CrapoL, GilbertW (1968) Mutants that make more lac repressor. Proc Natl Acad Sci USA 59: 1259–1264.

43. HalfmannR, JaroszDF, JonesSK, ChangA, LancasterAK, et al. (2012) Prions are a common mechanism for phenotypic inheritance in wild yeasts. Nature 482: 363–368 doi:10.1038/nature10875

44. van LeeuwenF, van der BeekE, SegerM, BurbachP, IvellR (1989) Age-related development of a heterozygous phenotype in solitary neurons of the homozygous Brattleboro rat. Proc Natl Acad Sci USA 86: 6417–6420.

45. BensonKF (2004) Paradoxical homozygous expression from heterozygotes and heterozygous expression from homozygotes as a consequence of transcriptional infidelity through a polyadenine tract in the AP3B1 gene responsible for canine cyclic neutropenia. Nucleic Acids Research 32: 6327–6333 doi:10.1093/nar/gkh974

46. TaddeiF, HayakawaH, BoutonM, CirinesiA, MaticI, et al. (1997) Counteraction by MutT protein of transcriptional errors caused by oxidative damage. Science 278: 128–130.

47. van LeeuwenFW (1998) Frameshift mutants of β amyloid precursor protein and Ubiquitin-B in Alzheimer's and Down patients. Science 279: 242–247 doi:10.1126/science.279.5348.242

48. NinioJ (1991) Connections between translation, transcription and replication error-rates. Biochimie 73: 1517–1523.

49. OzbudakEM, BecskeiA, van OudenaardenA (2005) A system of counteracting feedback loops regulates Cdc42p activity during spontaneous cell polarization. Developmental Cell 9: 565–571 doi:10.1016/j.devcel.2005.08.014

50. WernetMF, MazzoniEO, ÇelikA, DuncanDM, DuncanI, et al. (2006) Stochastic spineless expression creates the retinal mosaic for colour vision. Nat Cell Biol 440: 174–180 doi:10.1038/nature04615

51. MacArthurBen D, Ma'ayanA, LemischkaIR (2009) Systems biology of stem cell fate and cellular reprogramming. Nat Rev Mol Cell Biol 10: 672–681 doi:10.1038/nrm2766

52. NachmanI, RamanathanS (2008) HIV-1 positive feedback and lytic fate. Nat Genet 40: 382–383 doi:10.1038/ng0408-382

53. TaniguchiY, ChoiPJ, LiGW, ChenH, BabuM, et al. (2010) Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells. Science 329: 533–538 doi:10.1126/science.1188308

54. HollandMJ (2002) Transcript abundance in yeast varies over six orders of magnitude. J Biol Chem 277: 14363–14366 doi:10.1074/jbc.C200101200

55. VelculescuVE, MaddenSL, ZhangL, LashAE, YuJ, et al. (1999) Analysis of human transcriptomes. Nat Genet 23: 387–388.

56. SigalA, MiloR, CohenA, Geva-ZatorskyN, KleinY, et al. (2006) Variability and memory of protein levels in human cells. Nature 444: 643–646 doi:10.1038/nature05316

57. JoplingC, BoueS, BelmonteJCI (2011) Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nat Rev Mol Cell Biol 12: 79–89 doi:10.1038/nrm3043

58. BrulliardM, LorphelinD, CollignonO, LorphelinW, ThouvenotB, et al. (2007) Nonrandom variations in human cancer ESTs indicate that mRNA heterogeneity increases during carcinogenesis. Proc Natl Acad Sci USA 104: 7522–7527 doi:10.1073/pnas.0611076104

59. DatsenkoKA, WannerBL (2000) One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc Natl Acad Sci USA 97: 6640–6645 doi:10.1073/pnas.120163297

60. OehlerS, EismannER, KrämerH, Müller-HillB (1990) The three operators of the lac operon cooperate in repression. EMBO J 9: 973–979.

61. PlattT, WeberK, GanemD, MillerJH (1972) Translational restarts: AUG reinitiation of a lac repressor fragment. Proc Natl Acad Sci USA 69: 897–901.

62. KleinaLG, MillerJH (1990) Genetic studies of the lac repressor. XIII. Extensive amino acid replacements generated by the use of natural and synthetic nonsense suppressors. J Mol Biol 212: 295–318 doi:10.1016/0022-2836(90)90126-7

63. ClarkeND, BeamerLJ, GoldbergHR, BerkowerC, PaboCO (1991) The DNA binding arm of lambda repressor: critical contacts from a flexible region. Science 254: 267–270.

64. SellittiMA, PavcoPA, SteegeDA (1987) lac repressor blocks in vivo transcription of lac control region DNA. Proc Natl Acad Sci USA 84: 3199–3203.

65. AboT, InadaT, OgawaK, AibaH (2000) SsrA-mediated tagging and proteolysis of LacI and its role in the regulation of lac operon. EMBO J 19: 3762–3769.