Combinatorial Gene Regulation through Kinetic Control of the Transcription Cycle.

Cells decide when, where, and to what level to express their genes by "computing" information from transcription factors (TFs) binding to regulatory DNA. How is the information contained in multiple TF-binding sites integrated to dictate the rate of transcription? The dominant conceptual and quantitative model is that TFs combinatorially recruit one another and RNA polymerase to the promoter by direct physical interactions. Here, we develop a quantitative framework to explore kinetic control, an alternative model in which combinatorial gene regulation can result from TFs working on different kinetic steps of the transcription cycle. Kinetic control can generate a wide range of analog and Boolean computations without requiring the input TFs to be simultaneously bound to regulatory DNA. We propose experiments that will illuminate the role of kinetic control in transcription and discuss implications for deciphering the cis-regulatory "code."

[1]  Zeba Wunderlich,et al.  Shadow enhancers enable Hunchback bifunctionality in the Drosophila embryo , 2015, Proceedings of the National Academy of Sciences.

[2]  J. Gelles,et al.  Mechanism of Transcription Initiation at an Activator-Dependent Promoter Defined by Single-Molecule Observation , 2012, Cell.

[3]  A. Pombo,et al.  Gene activation by metazoan enhancers: Diverse mechanisms stimulate distinct steps of transcription , 2016, BioEssays : news and reviews in molecular, cellular and developmental biology.

[4]  M. Carey,et al.  The Enhanceosome and Transcriptional Synergy , 1998, Cell.

[5]  Thomas Zichner,et al.  Shadow Enhancers Are Pervasive Features of Developmental Regulatory Networks , 2016, Current Biology.

[6]  Rob Phillips,et al.  Quantitative dissection of the simple repression input–output function , 2011, Proceedings of the National Academy of Sciences.

[7]  T. Maniatis,et al.  Virus induction of human IFNβ gene expression requires the assembly of an enhanceosome , 1995, Cell.

[8]  J. Peccoud,et al.  Markovian Modeling of Gene-Product Synthesis , 1995 .

[9]  Terence Hwa,et al.  Transcriptional regulation by the numbers: models. , 2005, Current opinion in genetics & development.

[10]  S. Nechaev,et al.  Pol II waiting in the starting gates: Regulating the transition from transcription initiation into productive elongation. , 2011, Biochimica et biophysica acta.

[11]  Venky N. Iyer,et al.  Sepsid even-skipped Enhancers Are Functionally Conserved in Drosophila Despite Lack of Sequence Conservation , 2008, PLoS genetics.

[12]  Eric H Davidson,et al.  Evolutionary bioscience as regulatory systems biology. , 2011, Developmental biology.

[13]  Julian R. E. Davis,et al.  Dynamic Analysis of Stochastic Transcription Cycles , 2011, PLoS biology.

[14]  W. Kraus,et al.  Ready, pause, go: regulation of RNA polymerase II pausing and release by cellular signaling pathways. , 2015, Trends in biochemical sciences.

[15]  D. Wassarman,et al.  Promoting developmental transcription , 2010, Development.

[16]  Fabiana M. Duarte,et al.  Transcription factors GAF and HSF act at distinct regulatory steps to modulate stress-induced gene activation , 2016, bioRxiv.

[17]  J Wang,et al.  A mathematical model for synergistic eukaryotic gene activation. , 1999, Journal of molecular biology.

[18]  Jané Kondev,et al.  Transcriptional control of noise in gene expression , 2008, Proceedings of the National Academy of Sciences.

[19]  Nacho Molina,et al.  Mammalian Genes Are Transcribed with Widely Different Bursting Kinetics , 2011, Science.

[20]  R. Veitia,et al.  A sigmoidal transcriptional response: cooperativity, synergy and dosage effects , 2003, Biological reviews of the Cambridge Philosophical Society.

[21]  E. Gonzalez-Couto,et al.  Synergistic and promoter-selective activation of transcription by recruitment of transcription factors TFIID and TFIIB. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  André L. Martins,et al.  Signaling pathways differentially affect RNA polymerase II initiation, pausing, and elongation rate in cells. , 2013, Molecular cell.

[23]  T. Kepler,et al.  Stochasticity in transcriptional regulation: origins, consequences, and mathematical representations. , 2001, Biophysical journal.

[24]  J. Shendure,et al.  Massively parallel decoding of mammalian regulatory sequences supports a flexible organizational model , 2013, Nature Genetics.

[25]  Kevin Struhl,et al.  Mechanisms for diversity in gene expression patterns , 1991, Neuron.

[26]  D. Bentley,et al.  Transcriptional elongation by RNA polymerase II is stimulated by transactivators , 1994, Cell.

[27]  Zeba Wunderlich,et al.  Krüppel Expression Levels Are Maintained through Compensatory Evolution of Shadow Enhancers. , 2015, Cell reports.

[28]  Zeba Wunderlich,et al.  Dissecting sources of quantitative gene expression pattern divergence between Drosophila species , 2012, Molecular systems biology.

[29]  D. Herschlag,et al.  Synergism in transcriptional activation: a kinetic view. , 1993, Genes & development.

[30]  J. Gagneur,et al.  TT-seq maps the human transient transcriptome , 2016, Science.

[31]  Rob Phillips,et al.  Effect of Promoter Architecture on the Cell-to-Cell Variability in Gene Expression , 2010, PLoS Comput. Biol..

[32]  J. T. Kadonaga,et al.  Enhancer-promoter specificity mediated by DPE or TATA core promoter motifs. , 2001, Genes & development.

[33]  Erin K O'Shea,et al.  Signal-dependent dynamics of transcription factor translocation controls gene expression , 2011, Nature Structural &Molecular Biology.

[34]  Z. Yakhini,et al.  Inferring gene regulatory logic from high-throughput measurements of thousands of systematically designed promoters , 2012, Nature Biotechnology.

[35]  Steven A. Brown,et al.  Transcriptional activation domains stimulate initiation and elongation at different times and via different residues , 1998, The EMBO journal.

[36]  Xin He,et al.  Thermodynamics-Based Models of Transcriptional Regulation by Enhancers: The Roles of Synergistic Activation, Cooperative Binding and Short-Range Repression , 2010, PLoS Comput. Biol..

[37]  M. Elowitz,et al.  Frequency-modulated nuclear localization bursts coordinate gene regulation , 2008, Nature.

[38]  Felix Naef,et al.  Structure of silent transcription intervals and noise characteristics of mammalian genes , 2015, Molecular systems biology.

[39]  S. Busby,et al.  The regulation of bacterial transcription initiation , 2004, Nature Reviews Microbiology.

[40]  C C Adams,et al.  Binding of disparate transcriptional activators to nucleosomal DNA is inherently cooperative , 1995, Molecular and cellular biology.

[41]  E. Segal,et al.  The grammar of transcriptional regulation , 2014, Human Genetics.

[42]  Joseph B Hiatt,et al.  Massively parallel functional dissection of mammalian enhancers in vivo , 2012, Nature Biotechnology.

[43]  A. Hinnebusch,et al.  Simultaneous Recruitment of Coactivators by Gcn4p Stimulates Multiple Steps of Transcription In Vivo , 2005, Molecular and Cellular Biology.

[44]  Omar P. Tabbaa,et al.  Dynamic control of gene regulatory logic by seemingly redundant transcription factors , 2016, eLife.

[45]  Michael R Green,et al.  Eukaryotic transcription activation: right on target. , 2005, Molecular cell.

[46]  A. Salvador,et al.  Synergism analysis of biochemical systems. I. Conceptual framework. , 2000, Mathematical biosciences.

[47]  Gerald Stampfel,et al.  Transcriptional regulators form diverse groups with context-dependent regulatory functions , 2015, Nature.

[48]  Nicolas E. Buchler,et al.  On schemes of combinatorial transcription logic , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[49]  E. Furlong,et al.  Transcription factors: from enhancer binding to developmental control , 2012, Nature Reviews Genetics.

[50]  B. Kholodenko,et al.  Versatility of Cooperative Transcriptional Activation: A Thermodynamical Modeling Analysis for Greater-Than-Additive and Less-Than-Additive Effects , 2012, PloS one.

[51]  E. Siggia,et al.  Analysis of Combinatorial cis-Regulation in Synthetic and Genomic Promoters , 2008, Nature.

[52]  Jane Kondev,et al.  Regulation of noise in gene expression. , 2013, Annual review of biophysics.

[53]  Sandeep Choubey,et al.  Deciphering Transcriptional Dynamics In Vivo by Counting Nascent RNA Molecules , 2013, PLoS Comput. Biol..

[54]  Hiroshi Kimura,et al.  Regulation of RNA polymerase II activation by histone acetylation in single living cells , 2014, Nature.

[55]  James J. Collins,et al.  Using Targeted Chromatin Regulators to Engineer Combinatorial and Spatial Transcriptional Regulation , 2014, Cell.

[56]  Cosmas D. Arnold,et al.  Quantitative genome-wide enhancer activity maps for five Drosophila species show functional enhancer conservation and turnover during cis-regulatory evolution , 2014, Nature Genetics.

[57]  A. Stathopoulos,et al.  Complex interactions between cis-regulatory modules in native conformation are critical for Drosophila snail expression , 2011, Development.

[58]  Marc S. Sherman,et al.  Thermodynamic State Ensemble Models of cis-Regulation , 2012, PLoS Comput. Biol..

[59]  Rob Phillips,et al.  Operator sequence alters gene expression independently of transcription factor occupancy in bacteria. , 2012, Cell reports.

[60]  A. E. Tsong,et al.  Evolution of alternative transcriptional circuits with identical logic , 2006, Nature.

[61]  John T. Lis,et al.  Defining mechanisms that regulate RNA polymerase II transcription in vivo , 2009, Nature.

[62]  Steven Hahn,et al.  Structure and mechanism of the RNA polymerase II transcription machinery , 2004, Nature Structural &Molecular Biology.

[63]  Eran Segal,et al.  Core promoter sequence in yeast is a major determinant of expression level , 2015, Genome research.

[64]  B. Cullen,et al.  Synergistic enhancement of both initiation and elongation by acidic transcription activation domains. , 1996, The EMBO journal.

[65]  H. Bussemaker,et al.  In search of the determinants of enhancer-promoter interaction specificity. , 2014, Trends in cell biology.

[66]  Christophe Zimmer,et al.  A single-molecule view of transcription reveals convoys of RNA polymerases and multi-scale bursting , 2016, Nature Communications.

[67]  T. Mikkelsen,et al.  Rapid dissection and model-based optimization of inducible enhancers in human cells using a massively parallel reporter assay , 2012, Nature Biotechnology.

[68]  Martin Fussenegger,et al.  Mammalian synthetic biology: engineering of sophisticated gene networks. , 2007, Journal of biotechnology.

[69]  J. Greenblatt,et al.  Three functional classes of transcriptional activation domain , 1996, Molecular and cellular biology.

[70]  Hernan G. Garcia,et al.  Transcriptional Regulation by the Numbers 2: Applications , 2004, q-bio/0412011.

[71]  Michael B. Elowitz,et al.  Combinatorial gene regulation by modulation of relative pulse timing , 2015, Nature.

[72]  Mark Groudine,et al.  A block to elongation is largely responsible for decreased transcription of c-myc in differentiated HL60 cells , 1986, Nature.

[73]  Rob Phillips,et al.  Tuning Promoter Strength through RNA Polymerase Binding Site Design in Escherichia coli , 2012, PLoS Comput. Biol..

[74]  Kevin Struhl,et al.  The transition between transcriptional initiation and elongation in E. coli is highly variable and often rate limiting. , 2006, Molecular cell.

[75]  Hernan G. Garcia,et al.  Enhancer additivity and non-additivity are determined by enhancer strength in the Drosophila embryo , 2015, eLife.

[76]  K. Struhl,et al.  The transition from transcriptional initiation to elongation. , 2008, Current opinion in genetics & development.

[77]  Rishi Garg,et al.  Controlling promoter strength and regulation in Saccharomyces cerevisiae using synthetic hybrid promoters , 2012, Biotechnology and bioengineering.