Synthetic Switches and Regulatory Circuits in Plants1[OPEN]

Theoretical-experimental approaches are described for the engineering of synthetic chemical- and light-regulated (optogenetic) switches and circuits for the targeted interrogation and control of cell processes. Synthetic biology is an established but ever-growing interdisciplinary field of research currently revolutionizing biomedicine studies and the biotech industry. The engineering of synthetic circuitry in bacterial, yeast, and animal systems prompted considerable advances for the understanding and manipulation of genetic and metabolic networks; however, their implementation in the plant field lags behind. Here, we review theoretical-experimental approaches to the engineering of synthetic chemical- and light-regulated (optogenetic) switches for the targeted interrogation and control of cellular processes, including existing applications in the plant field. We highlight the strategies for the modular assembly of genetic parts into synthetic circuits of different complexity, ranging from Boolean logic gates and oscillatory devices up to semi- and fully synthetic open- and closed-loop molecular and cellular circuits. Finally, we explore potential applications of these approaches for the engineering of novel functionalities in plants, including understanding complex signaling networks, improving crop productivity, and the production of biopharmaceuticals.

[1]  Andreja Majerle,et al.  A bistable genetic switch based on designable DNA-binding domains , 2014, Nature Communications.

[2]  Andreja Majerle,et al.  Designable DNA-binding domains enable construction of logic circuits in mammalian cells. , 2014, Nature chemical biology.

[3]  M. Fussenegger,et al.  Designing cell function: assembly of synthetic gene circuits for cell biology applications , 2018, Nature Reviews Molecular Cell Biology.

[4]  Jared E. Toettcher,et al.  A synthetic–natural hybrid oscillator in human cells , 2010, Proceedings of the National Academy of Sciences.

[5]  E. Agosin,et al.  Optogenetic switches for light-controlled gene expression in yeast , 2017, Applied Microbiology and Biotechnology.

[6]  M. di Bernardo,et al.  A comparative analysis of synthetic genetic oscillators , 2010, Journal of The Royal Society Interface.

[7]  Mauricio S. Antunes,et al.  Programmable Ligand Detection System in Plants through a Synthetic Signal Transduction Pathway , 2011, PloS one.

[8]  J. Hasty,et al.  Synthetic gene network for entraining and amplifying cellular oscillations. , 2002, Physical review letters.

[9]  J. Collins,et al.  Construction of a genetic toggle switch in Escherichia coli , 2000, Nature.

[10]  Donald R. Ort,et al.  Synthetic glycolate metabolism pathways stimulate crop growth and productivity in the field , 2019, Science.

[11]  Alexander M. Jones,et al.  Genetically Encoded Biosensors in Plants: Pathways to Discovery. , 2018, Annual review of plant biology.

[12]  B. Goodwin Oscillatory behavior in enzymatic control processes. , 1965, Advances in enzyme regulation.

[13]  A. Ferré-D’Amaré,et al.  Structural basis for specific, high-affinity tetracycline binding by an in vitro evolved aptamer and artificial riboswitch. , 2008, Chemistry & biology.

[14]  Wilfried Weber,et al.  OptoBase: A Web Platform for Molecular Optogenetics. , 2018, ACS synthetic biology.

[15]  W. Reznikoff,et al.  Genetic regulation: the Lac control region. , 1975, Science.

[16]  Araceli M. Huerta,et al.  From specific gene regulation to genomic networks: a global analysis of transcriptional regulation in Escherichia coli. , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[17]  M. Fussenegger,et al.  Macrolide-based transgene control in mammalian cells and mice , 2002, Nature Biotechnology.

[18]  Christopher A. Voigt,et al.  Multi-input CRISPR/Cas genetic circuits that interface host regulatory networks , 2014, Molecular systems biology.

[19]  Martin Fussenegger,et al.  Synthetic RNA-based switches for mammalian gene expression control. , 2017, Current opinion in biotechnology.

[20]  Michael Z. Lin,et al.  Optical control of biological processes by light‐switchable proteins , 2015, Wiley interdisciplinary reviews. Developmental biology.

[21]  M. Gossen,et al.  Transcriptional activation by tetracyclines in mammalian cells. , 1995, Science.

[22]  Trevor E Swartz,et al.  Structural basis of photosensitivity in a bacterial light-oxygen-voltage/helix-turn-helix (LOV-HTH) DNA-binding protein , 2011, Proceedings of the National Academy of Sciences.

[23]  The alc-GR System. A Modified alc Gene Switch Designed for Use in Plant Tissue Culture1[w] , 2005, Plant Physiology.

[24]  G. Crabtree,et al.  NFAT Signaling Choreographing the Social Lives of Cells , 2002, Cell.

[25]  M. Gossen,et al.  A chimeric transactivator allows tetracycline-responsive gene expression in whole plants. , 1994, The Plant journal : for cell and molecular biology.

[26]  Detlef Weigel,et al.  Highly Specific Gene Silencing by Artificial MicroRNAs in Arabidopsis[W][OA] , 2006, The Plant Cell Online.

[27]  U. Sonnewald,et al.  An ethanol inducible gene switch for plants used to manipulate carbon metabolism , 1998, Nature Biotechnology.

[28]  K. Haynes,et al.  Can the Natural Diversity of Quorum-Sensing Advance Synthetic Biology? , 2015, Front. Bioeng. Biotechnol..

[29]  L. Serrano,et al.  Engineering stability in gene networks by autoregulation , 2000, Nature.

[30]  Karl Deisseroth,et al.  The form and function of channelrhodopsin , 2017, Science.

[31]  Gábor Balázsi,et al.  Transferring a synthetic gene circuit from yeast to mammalian cells , 2013, Nature Communications.

[32]  Jim Haseloff,et al.  Spatial control of transgene expression in rice (Oryza sativa L.) using the GAL4 enhancer trapping system. , 2005, The Plant journal : for cell and molecular biology.

[33]  U. Grossniklaus,et al.  A Gateway Cloning Vector Set for High-Throughput Functional Analysis of Genes in Planta[w] , 2003, Plant Physiology.

[34]  Mauricio S. Antunes,et al.  A synthetic de-greening gene circuit provides a reporting system that is remotely detectable and has a re-set capacity. , 2006, Plant biotechnology journal.

[35]  Alexander R Leydon,et al.  Synthetic hormone-responsive transcription factors can monitor and re-program plant development , 2017, bioRxiv.

[36]  A. Fire,et al.  Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans , 1998, Nature.

[37]  Wendell A Lim,et al.  Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities. , 2017, Annual review of immunology.

[38]  Christopher A. Voigt,et al.  Genetic programs constructed from layered logic gates in single cells , 2012, Nature.

[39]  M. Fussenegger,et al.  A Synthetic Optogenetic Transcription Device Enhances Blood-Glucose Homeostasis in Mice , 2011, Science.

[40]  Jared E. Toettcher,et al.  Using Optogenetics to Interrogate the Dynamic Control of Signal Transmission by the Ras/Erk Module , 2013, Cell.

[41]  Roland Eils,et al.  Optogenetic control of nuclear protein export , 2016, Nature Communications.

[42]  W. Hillen,et al.  The role of the N terminus in Tet repressor for tet operator binding determined by a mutational analysis. , 1992, The Journal of biological chemistry.

[43]  W. Filipowicz,et al.  Tethering of human Ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis. , 2004, RNA.

[44]  Andrew J. Millar,et al.  Modelling the widespread effects of TOC1 signalling on the plant circadian clock and its outputs , 2013, BMC Systems Biology.

[45]  H. Bujard,et al.  Independent and tight regulation of transcriptional units in Escherichia coli via the LacR/O, the TetR/O and AraC/I1-I2 regulatory elements. , 1997, Nucleic acids research.

[46]  Matias D. Zurbriggen,et al.  Synthetic strategies for plant signalling studies: molecular toolbox and orthogonal platforms. , 2016, The Plant journal : for cell and molecular biology.

[47]  Jens Timmer,et al.  A red/far-red light-responsive bi-stable toggle switch to control gene expression in mammalian cells , 2013, Nucleic acids research.

[48]  Markus Wieland,et al.  Programmable single-cell mammalian biocomputers , 2012, Nature.

[49]  Wendell A. Lim,et al.  Designing customized cell signalling circuits , 2010, Nature Reviews Molecular Cell Biology.

[50]  J. Medford,et al.  Towards programmable plant genetic circuits. , 2016, The Plant journal : for cell and molecular biology.

[51]  L. Laplaze,et al.  GAL4-GFP enhancer trap lines for genetic manipulation of lateral root development in Arabidopsis thaliana. , 2005, Journal of experimental botany.

[52]  Chris Parker,et al.  Observations on the current status of Orobanche and Striga problems worldwide. , 2009, Pest management science.

[53]  J. Liao,et al.  A synthetic gene–metabolic oscillator , 2005, Nature.

[54]  Alexander R Leydon,et al.  Synthetic hormone-responsive transcription factors can monitor and reprogram plant development , 2017, bioRxiv.

[55]  Sindy K. Y. Tang,et al.  Programming self-organizing multicellular structures with synthetic cell-cell signaling , 2018, Science.

[56]  T. Kagawa,et al.  Phototropin and light-signaling in phototropism. , 2006, Current opinion in plant biology.

[57]  W. Weber,et al.  Molecular switches in animal cells , 2012, FEBS letters.

[58]  J. Stelling,et al.  A tunable synthetic mammalian oscillator , 2009, Nature.

[59]  Bernard Chasan Physical Biology of the Cell , 2010 .

[60]  Josephine R. Chandler,et al.  Bacterial Quorum Sensing and Microbial Community Interactions , 2018, mBio.

[61]  Miguel Fernández-Niño,et al.  A synthetic multi-cellular network of coupled self-sustained oscillators , 2017, PloS one.

[62]  Katja E. Jaeger,et al.  Interlocking Feedback Loops Govern the Dynamic Behavior of the Floral Transition in Arabidopsis[W][OA] , 2013, Plant Cell.

[63]  Wusheng Liu,et al.  Advanced genetic tools for plant biotechnology , 2013, Nature Reviews Genetics.

[64]  Wusheng Liu,et al.  Plant synthetic biology. , 2015, Trends in plant science.

[65]  F. Lienert,et al.  Synthetic biology in mammalian cells: next generation research tools and therapeutics , 2014, Nature Reviews Molecular Cell Biology.

[66]  B. Cui,et al.  Optogenetic control of intracellular signaling pathways. , 2015, Trends in biotechnology.

[67]  J. Collins,et al.  DIVERSITY-BASED, MODEL-GUIDED CONSTRUCTION OF SYNTHETIC GENE NETWORKS WITH PREDICTED FUNCTIONS , 2009, Nature Biotechnology.

[68]  Kevin Thurley,et al.  Modeling Cell-to-Cell Communication Networks Using Response-Time Distributions , 2018, Cell systems.

[69]  Mauricio Barahona,et al.  Computational Re-Design of Synthetic Genetic Oscillators for Independent Amplitude and Frequency Modulation , 2017, bioRxiv.

[70]  Brian F. Volkman,et al.  Agrochemical control of plant water use using engineered abscisic acid receptors , 2015, Nature.

[71]  M. Mahfouz,et al.  RNA-guided transcriptional regulation in planta via synthetic dCas9-based transcription factors. , 2015, Plant biotechnology journal.

[72]  Diego Orzaez,et al.  DNA assembly standards: Setting the low-level programming code for plant biotechnology. , 2018, Plant science : an international journal of experimental plant biology.

[73]  Mett,et al.  Controlled cytokinin production in transgenic tobacco using a copper-inducible promoter , 1998, Plant physiology.

[74]  James M. Carothers,et al.  Digital logic circuits in yeast with CRISPR-dCas9 NOR gates , 2017, Nature Communications.

[75]  B. Bassler,et al.  Quorum sensing in bacteria. , 2001, Annual review of microbiology.

[76]  W. J. Brammar,et al.  Control of gene expression in tobacco cells using a bacterial operator‐repressor system. , 1992, The EMBO journal.

[77]  James A. Stapleton,et al.  Quantitative and simultaneous translational control of distinct mammalian mRNAs , 2013, Nucleic acids research.

[78]  Jens Timmer,et al.  Multi-chromatic control of mammalian gene expression and signaling , 2013, Nucleic acids research.

[79]  N. Rockwell,et al.  The Structure of Phytochrome: A Picture Is Worth a Thousand Spectra , 2006, The Plant Cell Online.

[80]  R. W. Davis,et al.  A steroid-inducible gene expression system for plant cells. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[81]  R. Quatrano,et al.  Use of Bacterial Quorum-Sensing Components to Regulate Gene Expression in Plants1[W] , 2006, Plant Physiology.

[82]  Lukas C. Kapitein,et al.  Optogenetic control of organelle transport and positioning , 2015, Nature.

[83]  M. Freeman Feedback control of intercellular signalling in development , 2000, Nature.

[84]  B. Goodwin Temporal Organization in Cells; a Dynamic Theory of Cellular Control Processes , 2015 .

[85]  Stuart L. Schreiber,et al.  SnapShot: Ca2+-Calcineurin-NFATSignaling , 2009, Cell.

[86]  Daniel F. Voytas,et al.  A CRISPR/Cas9 Toolbox for Multiplexed Plant Genome Editing and Transcriptional Regulation1[OPEN] , 2015, Plant Physiology.

[87]  Matias D Zurbriggen,et al.  Red Light-Regulated Reversible Nuclear Localization of Proteins in Mammalian Cells and Zebrafish. , 2015, ACS synthetic biology.

[88]  Viktor Stein,et al.  Synthetic protein switches: design principles and applications. , 2015, Trends in biotechnology.

[89]  M. White,et al.  Characterization of the ethanol-inducible alc gene-expression system in Arabidopsis thaliana. , 2001, The Plant journal : for cell and molecular biology.

[90]  M. Fussenegger,et al.  Novel pristinamycin-responsive expression systems for plant cells. , 2001, Biotechnology and bioengineering.

[91]  Sung Mi Park,et al.  Translation initiation mediated by RNA looping , 2015, Proceedings of the National Academy of Sciences.

[92]  Klaus Palme,et al.  A quantitative ratiometric sensor for time-resolved analysis of auxin dynamics , 2013, Scientific Reports.

[93]  James J. Collins,et al.  Next-Generation Synthetic Gene Networks , 2009, Nature Biotechnology.

[94]  C. Gersbach,et al.  A light-inducible CRISPR/Cas9 system for control of endogenous gene activation , 2015, Nature chemical biology.

[95]  Matias D. Zurbriggen,et al.  Quantitatively Understanding Plant Signaling: Novel Theoretical-Experimental Approaches. , 2017, Trends in plant science.

[96]  Matias D. Zurbriggen,et al.  A Green-Light-Responsive System for the Control of Transgene Expression in Mammalian and Plant Cells. , 2018, ACS synthetic biology.

[97]  Alexander M. Jones,et al.  Quantitative imaging with fluorescent biosensors. , 2012, Annual review of plant biology.

[98]  Matias D. Zurbriggen,et al.  Optogenetics in Plants: Red/Far-Red Light Control of Gene Expression. , 2016, Methods in molecular biology.

[99]  M. Gossen,et al.  Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[100]  C. Gatz,et al.  Stringent repression and homogeneous de-repression by tetracycline of a modified CaMV 35S promoter in intact transgenic tobacco plants. , 1992, The Plant journal : for cell and molecular biology.

[101]  J. V. Van Etten,et al.  Human Pumilio Proteins Recruit Multiple Deadenylases to Efficiently Repress Messenger RNAs* , 2012, The Journal of Biological Chemistry.

[102]  U. Schopfer,et al.  Chemically Regulated Zinc Finger Transcription Factors* , 2000, The Journal of Biological Chemistry.

[103]  S. Cutler,et al.  A Rationally Designed Agonist Defines Subfamily IIIA Abscisic Acid Receptors As Critical Targets for Manipulating Transpiration. , 2017, ACS chemical biology.

[104]  Daniel Karcher,et al.  Inducible gene expression from the plastid genome by a synthetic riboswitch , 2010, Proceedings of the National Academy of Sciences.

[105]  B. Séraphin,et al.  Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion , 2001, The EMBO journal.

[106]  Mingqi Xie,et al.  Self-adjusting synthetic gene circuit for correcting insulin resistance , 2016, Nature Biomedical Engineering.

[107]  N. Chua,et al.  A glucocorticoid-mediated transcriptional induction system in transgenic plants. , 1997, The Plant journal : for cell and molecular biology.

[108]  G. Balázsi,et al.  Negative autoregulation linearizes the dose–response and suppresses the heterogeneity of gene expression , 2009, Proceedings of the National Academy of Sciences.

[109]  J. Szostak,et al.  In vitro selection of RNA molecules that bind specific ligands , 1990, Nature.

[110]  M. Bennett,et al.  A fast, robust, and tunable synthetic gene oscillator , 2008, Nature.

[111]  Carl Troein,et al.  Rethinking Transcriptional Activation in the Arabidopsis Circadian Clock , 2014, PLoS Comput. Biol..

[112]  Kole T. Roybal,et al.  Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors , 2016, Cell.

[113]  Thomas Lübberstedt,et al.  Need for multidisciplinary research towards a second green revolution. , 2005, Current opinion in plant biology.

[114]  Martin Fussenegger,et al.  BioLogic gates enable logical transcription control in mammalian cells , 2004, Biotechnology and bioengineering.

[115]  E. Greenberg,et al.  Quorum sensing in bacteria: the LuxR-LuxI family of cell density-responsive transcriptional regulators , 1994, Journal of bacteriology.

[116]  Ralf Reski,et al.  A red light-controlled synthetic gene expression switch for plant systems. , 2014, Molecular bioSystems.

[117]  A. Tramontano,et al.  A synthetic biology approach allows inducible retrotransposition in whole plants , 2010, Systems and Synthetic Biology.

[118]  Stefanie Widder,et al.  A generalized model of the repressilator , 2006, Journal of mathematical biology.

[119]  R. Weiss,et al.  Multi-input Rnai-based Logic Circuit for Identification of Specific , 2022 .

[120]  Moritoshi Sato,et al.  CRISPR-Cas9-based photoactivatable transcription system. , 2015, Chemistry & biology.

[121]  Nicholas J. Guido,et al.  A bottom-up approach to gene regulation , 2006, Nature.

[122]  Mauricio S. Antunes,et al.  Quantitative characterization of genetic parts and circuits for plant synthetic biology , 2015, Nature Methods.

[123]  S. Cutler,et al.  Chemical manipulation of plant water use. , 2016, Bioorganic & medicinal chemistry.

[124]  M. Fussenegger,et al.  Prosthetic gene networks as an alternative to standard pharmacotherapies for metabolic disorders. , 2015, Current opinion in biotechnology.

[125]  Mustafa Khammash,et al.  Design of a synthetic integral feedback circuit: dynamic analysis and DNA implementation , 2016, ACS synthetic biology.

[126]  T. Tuschl,et al.  Identification of Novel Genes Coding for Small Expressed RNAs , 2001, Science.

[127]  Brendan M Ryback,et al.  Design and analysis of a tunable synchronized oscillator , 2013, Journal of biological engineering.

[128]  Vladislav V Verkhusha,et al.  An optogenetic system based on bacterial phytochrome controllable with near-infrared light , 2016, Nature Methods.

[129]  K. Gardner,et al.  An optogenetic gene expression system with rapid activation and deactivation kinetics , 2013, Nature chemical biology.

[130]  Peter Hedden,et al.  Gibberellin biosynthesis and its regulation. , 2012, The Biochemical journal.

[131]  C. Robertson McClung,et al.  Plant Circadian Rhythms , 2006, The Plant Cell Online.

[132]  Ivan Razinkov,et al.  Sensing array of radically coupled genetic biopixels , 2011, Nature.

[133]  R. Poethig,et al.  GAL 4 GFP enhancer trap lines for analysis of stomatal guard cell development and gene expression , 2009 .

[134]  Nicola J Patron,et al.  DNA assembly for plant biology: techniques and tools. , 2014, Current opinion in plant biology.

[135]  Duško Lainšček,et al.  A Synthetic Mammalian Therapeutic Gene Circuit for Sensing and Suppressing Inflammation. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[136]  Wendell A Lim,et al.  Complex transcriptional modulation with orthogonal and inducible dCas9 regulators , 2016, Nature Methods.

[137]  J. Barbé,et al.  A multifunctional gene (tetR) controls Tn10-encoded tetracycline resistance , 1982, Journal of bacteriology.

[138]  Randall J. Platt,et al.  Optical Control of Mammalian Endogenous Transcription and Epigenetic States , 2013, Nature.

[139]  M. Elowitz,et al.  A synthetic oscillatory network of transcriptional regulators , 2000, Nature.

[140]  R. Eils,et al.  Engineering light-inducible nuclear localization signals for precise spatiotemporal control of protein dynamics in living cells , 2014, Nature Communications.

[141]  A. Webb,et al.  GAL4 GFP enhancer trap lines for analysis of stomatal guard cell development and gene expression , 2008, Journal of experimental botany.

[142]  L. Tsimring,et al.  A synchronized quorum of genetic clocks , 2009, Nature.

[143]  M. Savageau Comparison of classical and autogenous systems of regulation in inducible operons , 1974, Nature.

[144]  A. Ninfa,et al.  Development of Genetic Circuitry Exhibiting Toggle Switch or Oscillatory Behavior in Escherichia coli , 2003, Cell.

[145]  M. Fussenegger,et al.  An engineered epigenetic transgene switch in mammalian cells , 2004, Nature Biotechnology.

[146]  D. C. Nelson,et al.  Smoke and Hormone Mirrors: Action and Evolution of Karrikin and Strigolactone Signaling. , 2016, Trends in genetics : TIG.

[147]  David A. Drubin,et al.  Rational design of memory in eukaryotic cells. , 2007, Genes & development.

[148]  Christopher A. Voigt,et al.  Robust multicellular computing using genetically encoded NOR gates and chemical ‘wires’ , 2011, Nature.

[149]  K. Akiyama,et al.  Plant sesquiterpenes induce hyphal branching in arbuscular mycorrhizal fungi , 2005, Nature.

[150]  Barbara Fink,et al.  Molecular analysis of a synthetic tetracycline-binding riboswitch. , 2005, RNA.

[151]  E. Farcot,et al.  Modeling plant development: from signals to gene networks. , 2015, Current opinion in plant biology.

[152]  Jonathan S. Dordick,et al.  Radio-Wave Heating of Iron Oxide Nanoparticles Can Regulate Plasma Glucose in Mice , 2012, Science.

[153]  T. Wandless,et al.  General method for regulating protein stability with light. , 2014, ACS chemical biology.

[154]  Jens Timmer,et al.  Dual-controlled optogenetic system for the rapid down-regulation of protein levels in mammalian cells , 2018, Scientific Reports.

[155]  G. Howe,et al.  Control of Carbon Assimilation and Partitioning by Jasmonate: An Accounting of Growth–Defense Tradeoffs , 2016, Plants.

[156]  Homme W Hellinga,et al.  Engineering key components in a synthetic eukaryotic signal transduction pathway , 2009, Molecular systems biology.

[157]  J. Monod,et al.  Genetic regulatory mechanisms in the synthesis of proteins. , 1961, Journal of molecular biology.

[158]  B. J. Clark Control of Gene Expression , 2004 .

[159]  A. Trewavas Green plants as intelligent organisms. , 2005, Trends in plant science.

[160]  R. Breaker Riboswitches and the RNA world. , 2012, Cold Spring Harbor perspectives in biology.

[161]  J. Collins,et al.  Programmable cells: interfacing natural and engineered gene networks. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[162]  Paolo Sassone-Corsi,et al.  A Web of Circadian Pacemakers , 2002, Cell.

[163]  Wilfried Weber,et al.  Synthetic biological approaches to optogenetically control cell signaling. , 2017, Current opinion in biotechnology.

[164]  R. Weiss,et al.  Programmed population control by cell–cell communication and regulated killing , 2004, Nature.

[165]  N. Chua,et al.  Technical advance: An estrogen receptor-based transactivator XVE mediates highly inducible gene expression in transgenic plants. , 2000, The Plant journal : for cell and molecular biology.

[166]  Christina D Smolke,et al.  Reprogramming Cellular Behavior with RNA Controllers Responsive to Endogenous Proteins , 2010, Science.

[167]  Arp Schnittger,et al.  Phenotypes on demand via switchable target protein degradation in multicellular organisms , 2016, Nature Communications.

[168]  E. Bateman,et al.  Autoregulation of eukaryotic transcription factors. , 1998, Progress in nucleic acid research and molecular biology.

[169]  Matias D Zurbriggen,et al.  Optogenetics for gene expression in mammalian cells , 2015, Biological chemistry.

[170]  Maria Karlsson,et al.  A synthetic mammalian network to compute population borders based on engineered reciprocal cell-cell communication , 2015, BMC Systems Biology.

[171]  Christopher A. Voigt,et al.  Principles of genetic circuit design , 2014, Nature Methods.

[172]  W. Stec,et al.  Differences among mechanisms of ribozyme-catalyzed reactions. , 2000, Current opinion in biotechnology.