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Synthetic approaches to study transcriptional networks and noise in mammalian systems

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Abstract

Synthetic biology aims to build new functional organisms and to rationally re-design existing ones by applying the engineering principle of modularity. Apart from building new life forms to perform technical applications, the approach of synthetic biology is useful to dissect complex biological phenomena into simple and easy to understand synthetic modules. Synthetic gene networks have been successfully implemented in prokaryotes and lower eukaryotes, with recent approaches moving ahead towards the mammalian environment. However, synthetic circuits in higher eukaryotes present a more challenging scenario, since its reliability is compromised because of the strong stochastic nature of transcription. Here, the authors review recent approaches that take advantage of the noisy response of synthetic regulatory circuits to learn key features of the complex machinery that orchestrates transcription in higher eukaryotes. Understanding the causes and consequences of biological noise will allow us to design more reliable mammalian synthetic circuits with revolutionary medical applications.

References

    1. 1)
      • P.E.M. Purnick , R. Weiss .
        1. Purnick, P.E.M., Weiss, R.: ‘The second wave of synthetic biology: from modules to systems’, Nat. Rev. Mol. Cell Biol., 2009, 10, pp. 410422.
        . Nat. Rev. Mol. Cell Biol. , 410 - 422
    2. 2)
      • C.M. Agapakis , P.A. Silver .
        2. Agapakis, C.M., Silver, P.A.: ‘Synthetic biology: exploring and exploiting genetic modularity through the design of novel biological networks’, Mol. BioSyst., 2009, 5, pp. 704713.
        . Mol. BioSyst. , 704 - 713
    3. 3)
      • E. Young , H. Alper .
        3. Young, E., Alper, H.: ‘Synthetic biology: tools to design, build, and optimize cellular processes’, J. Biomed. Biotechnol., 2010, 2010, pp. 130781.
        . J. Biomed. Biotechnol. , 130781
    4. 4)
      • E. Andrianantoandro , S. Basu , D.K. Karig , R. Weiss .
        4. Andrianantoandro, E., Basu, S., Karig, D.K., Weiss, R.: ‘Synthetic biology: new engineering rules for an emerging discipline’, Mol. Syst. Biol., 2006, 2, pp. 2006.0028.
        . Mol. Syst. Biol. , 2006.0028
    5. 5)
      • S. Mukherji , A. van Oudenaarden .
        5. Mukherji, S., van Oudenaarden, A.: ‘Synthetic biology: understanding biological design from synthetic circuits’, Nat. Rev. Genet., 2009, 10, pp. 859871.
        . Nat. Rev. Genet. , 859 - 871
    6. 6)
      • S.A. Benner , A.M. Sismour .
        6. Benner, S.A., Sismour, A.M.: ‘Synthetic biology’, Nat. Rev. Genet., 2005, 6, pp. 533543.
        . Nat. Rev. Genet. , 533 - 543
    7. 7)
      • T.S. Gardner , C.R. Cantor , J.J. Collins .
        7. Gardner, T.S., Cantor, C.R., Collins, J.J.: ‘Construction of a genetic toggle switch in Escherichia coli’, Nature, 2000, 403, pp. 339342.
        . Nature , 339 - 342
    8. 8)
      • M.B. Elowitz , S. Leibler .
        8. Elowitz, M.B., Leibler, S.: ‘A synthetic oscillatory network of transcriptional regulators’, Nature, 2000, 403, pp. 335338.
        . Nature , 335 - 338
    9. 9)
      • A. Raj , A. van Oudenaarden .
        9. Raj, A., van Oudenaarden, A.: ‘Nature, nurture, or chance: stochastic gene expression and its consequences’, Cell, 2008, 135, pp. 216226.
        . Cell , 216 - 226
    10. 10)
      • M.B. Elowitz , A.J. Levine , E.D. Siggia , P.S. Swain .
        10. Elowitz, M.B., Levine, A.J., Siggia, E.D., Swain, P.S.: ‘Stochastic gene expression in a single cell’, Science, 2002, 297, pp. 11831186.
        . Science , 1183 - 1186
    11. 11)
      • W.J. Blake , M. Kaern , C.R. Cantor , J.J. Collins .
        11. Blake, W.J., Kaern, M., Cantor, C.R., Collins, J.J.: ‘Noise in eukaryotic gene expression’, Nature, 2003, 422, pp. 633637.
        . Nature , 633 - 637
    12. 12)
      • A. Raj , C.S. Peskin , D. Tranchina , D.Y. Vargas , S. Tyagi .
        12. Raj, A., Peskin, C.S., Tranchina, D., Vargas, D.Y., Tyagi, S.: ‘Stochastic mRNA synthesis in mammalian cells’, PLoS Biol., 2006, 4, pp. e309.
        . PLoS Biol. , e309
    13. 13)
      • L. Cai , N. Friedman , X.S. Xie .
        13. Cai, L., Friedman, N., Xie, X.S.: ‘Stochastic protein expression in individual cells at the single molecule level’, Nature, 2006, 440, pp. 358362.
        . Nature , 358 - 362
    14. 14)
      • G. Karlebach , R. Shamir .
        14. Karlebach, G., Shamir, R.: ‘Modelling and analysis of gene regulatory networks’, Nat. Rev. Mol. Cell Biol., 2008, 9, pp. 770780.
        . Nat. Rev. Mol. Cell Biol. , 770 - 780
    15. 15)
      • J. Peccoud , B. Ycart .
        15. Peccoud, J., Ycart, B.: ‘Markovian modeling of gene-product synthesis’, Theor. Population Biol., 1995, 48, pp. 222234.
        . Theor. Population Biol. , 222 - 234
    16. 16)
      • J.M. Pedraza , J. Paulsson .
        16. Pedraza, J.M., Paulsson, J.: ‘Effects of molecular memory and bursting on fluctuations in gene expression’, Science, 2008, 319, pp. 339343.
        . Science , 339 - 343
    17. 17)
      • R. Karmakar , I. Bose .
        17. Karmakar, R., Bose, I.: ‘Graded and binary responses in stochastic gene expression’, Phys. Biol., 2004, 1, pp. 197204.
        . Phys. Biol. , 197 - 204
    18. 18)
      • I.L. Ross , C.M. Browne , D.A. Hume .
        18. Ross, I.L., Browne, C.M., Hume, D.A.: ‘Transcription of individual genes in eukaryotic cells occurs randomly and infrequently’, Immunology  Cell Biol., 1994, 72, pp. 177185.
        . Immunology  Cell Biol. , 177 - 185
    19. 19)
      • S. Newlands , L.K. Levitt , C.S. Robinson .
        19. Newlands, S., Levitt, L.K., Robinson, C.S., et al: ‘Transcription occurs in pulses in muscle fibers’, Genes  Dev., 1998, 12, pp. 27482758.
        . Genes  Dev. , 2748 - 2758
    20. 20)
      • A. Becskei , B.B. Kaufmann , A. van Oudenaarden .
        20. Becskei, A., Kaufmann, B.B., van Oudenaarden, A.: ‘Contributions of low molecule number and chromosomal positioning to stochastic gene expression’, Nat. Genetics, 2005, 37, pp. 937944.
        . Nat. Genetics , 937 - 944
    21. 21)
      • G.L. Hager , J.G. McNally , T. Misteli .
        21. Hager, G.L., McNally, J.G., Misteli, T.: ‘Transcription dynamics’, Mol. Cell, 2009, 35, pp. 741753.
        . Mol. Cell , 741 - 753
    22. 22)
      • I.A. Swinburne , P.A. Silver .
        22. Swinburne, I.A., Silver, P.A.: ‘Intron delays and transcriptional timing during development’, Dev. Cell, 2008, 14, pp. 324330.
        . Dev. Cell , 324 - 330
    23. 23)
      • J.R. Manak , S. Dike , V. Sementchenko .
        23. Manak, J.R., Dike, S., Sementchenko, V., et al: ‘Biological function of unannotated transcription during the early development of Drosophila melanogaster’, Nat. Genetics, 2006, 38, pp. 11511158.
        . Nat. Genetics , 1151 - 1158
    24. 24)
      • I.A. Swinburne , D.G. Miguez , D. Landgraf , P.A. Silver .
        24. Swinburne, I.A., Miguez, D.G., Landgraf, D., Silver, P.A.: ‘Intron length increases oscillatory periods of gene expression in animal cells’, Genes  Dev., 2008, 22, pp. 23422346.
        . Genes  Dev. , 2342 - 2346
    25. 25)
      • J. Lewis .
        25. Lewis, J.: ‘Autoinhibition with transcriptional delay: a simple mechanism for the zebrafish somitogenesis oscillator’, Curr. Biol., 2003, 13, pp. 13981408.
        . Curr. Biol. , 1398 - 1408
    26. 26)
      • A. Goldbeter .
        26. Goldbeter, A.: ‘Computational approaches to cellular rhythms’, Nature, 2002, 420, pp. 238245.
        . Nature , 238 - 245
    27. 27)
      • M.D. Wang .
        27. Wang, M.D.: ‘Force and velocity measured for single molecules of RNA polymerase’, Science, 1998, 282, pp. 902907.
        . Science , 902 - 907
    28. 28)
      • K. Adelman , A. La Porta , T.J. Santangelo , J.T. Lis , J.W. Roberts , M.D. Wang .
        28. Adelman, K., La Porta, A., Santangelo, T.J., Lis, J.T., Roberts, J.W., Wang, M.D.: ‘Single molecule analysis of RNA polymerase elongation reveals uniform kinetic behavior’. Proc. National Academy of Sciences of the United States of America, October 2002, vol. 99, pp. 1353813543.
        . Proc. National Academy of Sciences of the United States of America , 13538 - 13543
    29. 29)
      • X. Darzacq , Y. Shav-Tal , V. de Turris .
        29. Darzacq, X., Shav-Tal, Y., de Turris, V., et al: ‘In vivo dynamics of RNA polymerase II transcription’, Nat. Struct. Mol. Biol., 2007, 14, pp. 796806.
        . Nat. Struct. Mol. Biol. , 796 - 806
    30. 30)
      • S.F. Tolic-Norrelykke .
        30. Tolic-Norrelykke, S.F.: ‘Diversity in the rates of transcript elongation by single RNA polymerase molecules’, J. Biol. Chem., 2003, 279, pp. 32923299.
        . J. Biol. Chem. , 3292 - 3299
    31. 31)
      • M.B. Ardehali , J.T. Lis .
        31. Ardehali, M.B., Lis, J.T.: ‘Tracking rates of transcription and splicing in vivo’, Nat. Struct. Mol. Biol., 2009, 16, pp. 11231124.
        . Nat. Struct. Mol. Biol. , 1123 - 1124
    32. 32)
      • D. Chandran , W. Copeland , S. Sleight , H. Sauro .
        32. Chandran, D., Copeland, W., Sleight, S., Sauro, H.: ‘Mathematical modeling and synthetic biology’, Drug Discov. Today: Disease Models, 2008, 5, pp. 299309.
        . Drug Discov. Today: Disease Models , 299 - 309
    33. 33)
      • J. Pedraza , A. van Oudenaarden .
        33. Pedraza, J., van Oudenaarden, A.: ‘Noise propagation in gene networks’, Sci. Signalling, 2005, 307, (March), pp. 19651969.
        . Sci. Signalling , 1965 - 1969
    34. 34)
      • W. Yu , M. Nomura , M. Ikeda .
        34. Yu, W., Nomura, M., Ikeda, M.: ‘Interactivating feedback loops within the mammalian clock: BMAL1 is negatively autoregulated and upregulated by CRY1, CRY2, and PER2’, Biochem. Biophys. Res. Commun., 2002, 290, pp. 933941.
        . Biochem. Biophys. Res. Commun. , 933 - 941
    35. 35)
      • N. Geva-Zatorsky , N. Rosenfeld , S. Itzkovitz .
        35. Geva-Zatorsky, N., Rosenfeld, N., Itzkovitz, S., et al: ‘Oscillations and variability in the p53 system’, Mol. Syst. Biol., 2006, 2, pp. 2006.0033.
        . Mol. Syst. Biol. , 2006.0033
    36. 36)
      • S. Serizawa , K. Miyamichi , H. Nakatani .
        36. Serizawa, S., Miyamichi, K., Nakatani, H., et al: ‘Negative feedback regulation ensures the one receptor-one olfactory neuron rule in mouse’, Science, 2003, 302, pp. 20882094.
        . Science , 2088 - 2094
    37. 37)
      • D. Angeli , J.E. Ferrell , E.D. Sontag .
        37. Angeli, D., Ferrell, J.E., Sontag, E.D.: ‘Detection of multistability, bifurcations, and hysteresis in a large class of biological positive-feedback systems’. Proc. National Academy of Sciences of the United States of America, February 2004, vol. 101, pp. 18221827.
        . Proc. National Academy of Sciences of the United States of America , 1822 - 1827
    38. 38)
      • D. Greber , M. Fussenegger .
        38. Greber, D., Fussenegger, M.: ‘Mammalian synthetic biology: engineering of sophisticated gene networks’, J. Biotechnol., 2007, 130, pp. 329345.
        . J. Biotechnol. , 329 - 345
    39. 39)
      • W. Xiong .
        39. Xiong, W.: ‘A positive-feedback-based bistable ‘memory module’ that governs a cell fate decision’, Nature, 2003, 426, (November), pp. 460465.
        . Nature , 460 - 465
    40. 40)
      • B.P. Kramer , M. Fussenegger .
        40. Kramer, B.P., Fussenegger, M.: ‘Hysteresis in a synthetic mammalian gene network’. Proc. National Academy of Sciences of the United States of America, July 2005, vol. 102, pp. 95179522.
        . Proc. National Academy of Sciences of the United States of America , 9517 - 9522
    41. 41)
      • T. May , M. Butueva , S. Bantner .
        41. May, T., Butueva, M., Bantner, S., et al: ‘Synthetic gene regulation circuits for control of cell expansion’, Tissue Eng. Part A, 2010, 16, pp. 441452.
        . Tissue Eng. Part A , 441 - 452
    42. 42)
      • D.R. Burrill , M.C. Inniss , P.M. Boyle , P.A. Silver .
        42. Burrill, D.R., Inniss, M.C., Boyle, P.M., Silver, P.A.: ‘Synthetic memory circuits for tracking human cell fate’, Genes  Dev., 2012, 26, pp. 14861497.
        . Genes  Dev. , 1486 - 1497
    43. 43)
      • A. Becskei , B. Séraphin , L. Serrano .
        43. Becskei, A., Séraphin, B., Serrano, L.: ‘Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion’,  EMBO J., 2001, 20, pp. 25282535.
        .  EMBO J. , 2528 - 2535
    44. 44)
      • F.J. Isaacs , J. Hasty , C.R. Cantor , J.J. Collins .
        44. Isaacs, F.J., Hasty, J., Cantor, C.R., Collins, J.J.: ‘Prediction and measurement of an autoregulatory genetic module’. Proc. National Academy of Sciences of the United States of America, June 2003, vol. 100, pp. 77147719.
        . Proc. National Academy of Sciences of the United States of America , 7714 - 7719
    45. 45)
      • W. Weber , M. Fussenegger .
        45. Weber, W., Fussenegger, M.: ‘Engineering of synthetic mammalian gene networks’, Chem.Biol., 2009, 16, pp. 287297.
        . Chem.Biol. , 287 - 297
    46. 46)
      • M.L. Simpson , C.D. Cox , G.S. Sayler .
        46. Simpson, M.L., Cox, C.D., Sayler, G.S.: ‘Frequency domain analysis of noise in autoregulated gene circuits’. Proc. National Academy of Sciences of the United States of America, April 2003, vol. 100, pp. 45514556.
        . Proc. National Academy of Sciences of the United States of America , 4551 - 4556
    47. 47)
      • J. Paulsson .
        47. Paulsson, J.: ‘Summing up the noise in gene networks’, Nature, 2004, 427, pp. 415418.
        . Nature , 415 - 418
    48. 48)
      • A. Becskei .
        48. Becskei, A.: ‘Engineering stability in gene networks by autoregulation’, Nature, 2000, (June), 405, pp. 590593.
        . Nature , 590 - 593
    49. 49)
      • D.W. Austin , M.S. Allen , J.M. McCollum .
        49. Austin, D.W., Allen, M.S., McCollum, J.M., et al: ‘Gene network shaping of inherent noise spectra’, Nature, 2006, 439, pp. 608611.
        . Nature , 608 - 611
    50. 50)
      • Y. Dublanche , K. Michalodimitrakis , N. Kümmerer , M. Foglierini , L. Serrano .
        50. Dublanche, Y., Michalodimitrakis, K., Kümmerer, N., Foglierini, M., Serrano, L.: ‘Noise in transcription negative feedback loops: simulation and experimental analysis’, Mol. Syst. Biol., 2006, 2, pp. 41.
        . Mol. Syst. Biol.
    51. 51)
      • N. Rosenfeld , M.B. Elowitz , U. Alon .
        51. Rosenfeld, N., Elowitz, M.B., Alon, U.: ‘Negative autoregulation speeds the response times of transcription networks’, J. Mol. Biol., 2002, 323, pp. 785793.
        . J. Mol. Biol. , 785 - 793
    52. 52)
      • A. Eldar , M.B. Elowitz .
        52. Eldar, A., Elowitz, M.B.: ‘Functional roles for noise in genetic circuits’, Nature, 2010, 467, pp. 167173.
        . Nature , 167 - 173
    53. 53)
      • M. Kaern , T.C. Elston , W.J. Blake , J.J. Collins .
        53. Kaern, M., Elston, T.C., Blake, W.J., Collins, J.J.: ‘Stochasticity in gene expression: from theories to phenotypes’, Nat. Rev. Genetics, 2005, 6, pp. 451464.
        . Nat. Rev. Genetics , 451 - 464
    54. 54)
      • M. Ptashne .
        54. Ptashne, M.: ‘On the use of the word ‘epigenetic’’, Curr. Biol.: CB, 2007, 17, pp. R233R236.
        . Curr. Biol.: CB , R233 - R236
    55. 55)
      • R. Steuer , C. Zhou , J. Kurths .
        55. Steuer, R., Zhou, C., Kurths, J.: ‘Constructive effects of uctuations in genetic and biochemical regulatory systems’, Biosystems, 2003, 72, pp. 241251.
        . Biosystems , 241 - 251
    56. 56)
      • J.R. Chabot , J.M. Pedraza , P. Luitel , A. van Oudenaarden .
        56. Chabot, J.R., Pedraza, J.M., Luitel, P., van Oudenaarden, A.: ‘Stochastic gene expression out-of-steady-state in the cyanobacterial circadian clock’, Nature, 2007, 450, pp. 12491252.
        . Nature , 1249 - 1252
    57. 57)
      • A. Colman-Lerner , A. Gordon , E. Serra .
        57. Colman-Lerner, A., Gordon, A., Serra, E., et al: ‘Regulated cell-to-cell variation in a cell-fate decision system’, Nature, 2005, 437, pp. 699706.
        . Nature , 699 - 706
    58. 58)
      • W. Weber , M. Fussenegger .
        58. Weber, W., Fussenegger, M.: ‘Synthetic gene networks in mammalian cells’, Curr. Opin. Biotechnol., 2010, 21, pp. 690696.
        . Curr. Opin. Biotechnol. , 690 - 696
    59. 59)
      • W. Weber , R. Schoenmakers , B. Keller .
        59. Weber, W., Schoenmakers, R., Keller, B., et al: ‘A synthetic mammalian gene circuit reveals antituberculosis compounds’, PNAS, 2008, 105, (29), pp. 99949998.
        . PNAS , 29 , 9994 - 9998
    60. 60)
      • J.C. Anderson , E.J. Clarke , A.P. Arkin , C.A. Voigt .
        60. Anderson, J.C., Clarke, E.J., Arkin, A.P., Voigt, C.A.: ‘Environmentally controlled invasion of cancer cells by engineered bacteria’, J. Mol. Biol., 2006, 355, pp. 619627.
        . J. Mol. Biol. , 619 - 627
    61. 61)
      • S. Xiang , J. Fruehauf , C.J. Li .
        61. Xiang, S., Fruehauf, J., Li, C.J.: ‘Short hairpin RNA-expressing bacteria elicit RNA interference in mammals’, Nat. Biotechnol., 2006, 24, pp. 697702.
        . Nat. Biotechnol. , 697 - 702
    62. 62)
      • M. Amidi , M. de Raad , D.J.A. Crommelin , W.E. Hennink , E. Mastrobattista .
        62. Amidi, M., de Raad, M., Crommelin, D.J.A., Hennink, W.E., Mastrobattista, E.: ‘Antigenexpressing immunostimulatory liposomes as a genetically programmable synthetic vaccine’, Syst. Synth. Biol., 2011, 5, pp. 2131.
        . Syst. Synth. Biol. , 21 - 31
    63. 63)
      • V. Gonzalez-Nicolini , C. Fux , M. Fussenegger .
        63. Gonzalez-Nicolini, V., Fux, C., Fussenegger, M.: ‘A novel mammalian cell-based approach for the discovery of anticancer drugs with reduced cytotoxicity on non-dividing cells’, Invest. New Drugs, 2004, 22, pp. 253262.
        . Invest. New Drugs , 253 - 262
    64. 64)
      • W. Weber , M. Fussenegger .
        64. Weber, W., Fussenegger, M.: ‘Pharmacologic transgene control systems for gene therapy’,  J.  Gene Med., 2006, 8, pp. 535556.
        .  J.  Gene Med. , 535 - 556
    65. 65)
      • W. Weber , M. Fussenegger .
        65. Weber, W., Fussenegger, M.: ‘Approaches for trigger-inducible viral transgene regulation in gene-based tissue engineering’, Curr. Opin. Biotechnol., 2004, 15, pp. 383391.
        . Curr. Opin. Biotechnol. , 383 - 391
    66. 66)
      • Y. Zheng , G. Sriram .
        66. Zheng, Y., Sriram, G.: ‘Mathematical modeling: bridging the gap between concept and realization in synthetic biology’, J. Biomed. Biotechnol., 2010, 2010, pp. 541609.
        . J. Biomed. Biotechnol. , 541609
    67. 67)
      • T. Ellis , X. Wang , J.J. Collins .
        67. Ellis, T., Wang, X., Collins, J.J.: ‘Diversity-based, model-guided construction of synthetic gene networks with predicted functions’, Nat. Biotechnol., 2009, 27, pp. 465471.
        . Nat. Biotechnol. , 465 - 471
    68. 68)
      • N. Nandagopal , M.B. Elowitz .
        68. Nandagopal, N., Elowitz, M.B.: ‘Synthetic biology: integrated gene circuits’, Science, 2011, 333, pp. 12441248.
        . Science , 1244 - 1248
    69. 69)
      • M. Gossen .
        69. Gossen, M.: ‘Tight control of gene expression in mammalian cells by tetracycline-responsive promoters’. Proc. National Academy of Sciences of the United States of America, 1992, vol. 89, June, pp. 55475551.
        . , 5547 - 5551
    70. 70)
      • D. Aubel , M. Fussenegger .
        70. Aubel, D., Fussenegger, M.: ‘Mammalian synthetic biology–from tools to therapies’, BioEssays: News  Rev. Mol., Cell. Dev. Biol., 2010, 32, pp. 332345.
        . BioEssays: News  Rev. Mol., Cell. Dev. Biol. , 332 - 345

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