Intrinsic Noise of microRNA-Regulated Genes and the ceRNA Hypothesis

MicroRNAs are small noncoding RNAs that regulate genes post-transciptionally by binding and degrading target eukaryotic mRNAs. We use a quantitative model to study gene regulation by inhibitory microRNAs and compare it to gene regulation by prokaryotic small non-coding RNAs (sRNAs). Our model uses a combination of analytic techniques as well as computational simulations to calculate the mean-expression and noise profiles of genes regulated by both microRNAs and sRNAs. We find that despite very different molecular machinery and modes of action (catalytic vs stoichiometric), the mean expression levels and noise profiles of microRNA-regulated genes are almost identical to genes regulated by prokaryotic sRNAs. This behavior is extremely robust and persists across a wide range of biologically relevant parameters. We extend our model to study crosstalk between multiple mRNAs that are regulated by a single microRNA and show that noise is a sensitive measure of microRNA-mediated interaction between mRNAs. We conclude by discussing possible experimental strategies for uncovering the microRNA-mRNA interactions and testing the competing endogenous RNA (ceRNA) hypothesis.

[1]  Michael Niepmann,et al.  microRNA-122 stimulates translation of hepatitis C virus RNA , 2008, The EMBO journal.

[2]  P. Pandolfi,et al.  A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language? , 2011, Cell.

[3]  G. Storz,et al.  Bacterial small RNA regulators: versatile roles and rapidly evolving variations. , 2011, Cold Spring Harbor perspectives in biology.

[4]  H. Bokhoven,et al.  MicroRNA networks direct neuronal development and plasticity , 2011, Cellular and Molecular Life Sciences.

[5]  Riccardo Zecchina,et al.  Modelling Competing Endogenous RNA Networks , 2013, PloS one.

[6]  H. Steller,et al.  Programmed Cell Death in Animal Development and Disease , 2011, Cell.

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

[8]  A. Oudenaarden,et al.  Cellular Decision Making and Biological Noise: From Microbes to Mammals , 2011, Cell.

[9]  Regulation by small RNAs via coupled degradation: mean-field and variational approaches. , 2011, Physical review. E, Statistical, nonlinear, and soft matter physics.

[10]  P. Swain,et al.  Intrinsic and extrinsic contributions to stochasticity in gene expression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  V. Ambros The functions of animal microRNAs , 2004, Nature.

[12]  A. Pasquinelli,et al.  MicroRNA assassins: factors that regulate the disappearance of miRNAs , 2010, Nature Structural &Molecular Biology.

[13]  Matteo Figliuzzi,et al.  MicroRNAs as a selective channel of communication between competing RNAs: a steady-state theory. , 2012, Biophysical journal.

[14]  E. Miska,et al.  MicroRNA functions in animal development and human disease , 2005, Development.

[15]  M. Niepmann Activation of hepatitis c virus translation by a liver-specific microRNA , 2009, Cell cycle.

[16]  Philipp Thomas,et al.  How accurate are the nonlinear chemical Fokker-Planck and chemical Langevin equations? , 2011, The Journal of chemical physics.

[17]  M. Selbach,et al.  Global quantification of mammalian gene expression control , 2011, Nature.

[18]  G. Storz,et al.  Regulatory RNAs in Bacteria , 2009, Cell.

[19]  G. Schratt microRNAs at the synapse , 2011, Nature Reviews Cancer.

[20]  K. Sneppen,et al.  Dynamic features of gene expression control by small regulatory RNAs , 2009, Proceedings of the National Academy of Sciences.

[21]  D. Sherrington Stochastic Processes in Physics and Chemistry , 1983 .

[22]  Joerg E Braun,et al.  GW182 proteins directly recruit cytoplasmic deadenylase complexes to miRNA targets. , 2011, Molecular cell.

[23]  T. Elston,et al.  Stochasticity in gene expression: from theories to phenotypes , 2005, Nature Reviews Genetics.

[24]  Peter T. McHale,et al.  Small Regulatory RNAs May Sharpen Spatial Expression Patterns , 2007, PLoS Comput. Biol..

[25]  R. Zecchina,et al.  Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments , 2013, Proceedings of the National Academy of Sciences.

[26]  Xuan Zhan,et al.  Intrinsic noise in post-transcriptional gene regulation by small non-coding RNA. , 2009, Biophysical chemistry.

[27]  Peter S Swain,et al.  Efficient attenuation of stochasticity in gene expression through post-transcriptional control. , 2004, Journal of molecular biology.

[28]  Grace X. Y. Zheng,et al.  MicroRNAs can generate thresholds in target gene expression , 2011, Nature Genetics.

[29]  Daniel T Gillespie,et al.  Stochastic simulation of chemical kinetics. , 2007, Annual review of physical chemistry.

[30]  J. Belasco All things must pass: contrasts and commonalities in eukaryotic and bacterial mRNA decay , 2010, Nature Reviews Molecular Cell Biology.

[31]  R. Kulkarni,et al.  Stochastic modeling of regulation of gene expression by multiple small RNAs. , 2011, Physical review. E, Statistical, nonlinear, and soft matter physics.

[32]  N. Wingreen,et al.  A quantitative comparison of sRNA-based and protein-based gene regulation , 2008, Molecular systems biology.

[33]  John D. Storey,et al.  Precision and functional specificity in mRNA decay , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  T. Hwa,et al.  Quantitative Characteristics of Gene Regulation by Small RNA , 2007, PLoS Biology.

[35]  B. Reinhart,et al.  MicroRNAs in plants. , 2002, Genes & development.

[36]  R. Kulkarni,et al.  Quantifying mRNA synthesis and decay rates using small RNAs. , 2009, Biophysical journal.

[37]  G. Storz,et al.  Regulation by small RNAs in bacteria: expanding frontiers. , 2011, Molecular cell.

[38]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[39]  E. Miska,et al.  How microRNAs control cell division, differentiation and death. , 2005, Current opinion in genetics & development.

[40]  D. Bartel,et al.  MicroRNAS and their regulatory roles in plants. , 2006, Annual review of plant biology.

[41]  E. Cox,et al.  Real-Time Kinetics of Gene Activity in Individual Bacteria , 2005, Cell.

[42]  R. Garzon,et al.  Micrornas: Emerging key regulators of hematopoiesis , 2010, American journal of hematology.

[43]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[44]  Arkady B. Khodursky,et al.  Global analysis of mRNA decay and abundance in Escherichia coli at single-gene resolution using two-color fluorescent DNA microarrays , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[45]  K. Jensen,et al.  The RNA chain elongation rate in Escherichia coli depends on the growth rate , 1994, Journal of bacteriology.

[46]  M. Thattai,et al.  Intrinsic noise in gene regulatory networks , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[47]  E. Baehrecke miRNAs: Micro Managers of Programmed Cell Death , 2003, Current Biology.

[48]  Carlos Caldas,et al.  Sizing up miRNAs as cancer genes , 2005, Nature Medicine.

[49]  S. Vasudevan,et al.  MicroRNA-mediated mRNA Translation Activation in Quiescent Cells and Oocytes Involves Recruitment of a Nuclear microRNP , 2012, Scientific Reports.

[50]  T. Hwa,et al.  Small RNAs establish gene expression thresholds. , 2008, Current opinion in microbiology.

[51]  J. M. Thomson,et al.  Argonaute2 Is the Catalytic Engine of Mammalian RNAi , 2004, Science.

[52]  J. Vogel,et al.  A new Vibrio cholerae sRNA modulates colonization and affects release of outer membrane vesicles , 2008, Molecular microbiology.

[53]  J. Vogel,et al.  Hfq and its constellation of RNA , 2011, Nature Reviews Microbiology.

[54]  H. Vaucheret,et al.  Form, Function, and Regulation of ARGONAUTE Proteins , 2010, Plant Cell.

[55]  Y. Hao,et al.  Theoretical analysis of catalytic-sRNA-mediated gene silencing. , 2011, Journal of molecular biology.

[56]  H. Bremer,et al.  Polypeptide-chain-elongation rate in Escherichia coli B/r as a function of growth rate. , 1976, The Biochemical journal.

[57]  D. Tranchina,et al.  Stochastic mRNA Synthesis in Mammalian Cells , 2006, PLoS biology.

[58]  D. Bartel,et al.  MicroRNAs Modulate Hematopoietic Lineage Differentiation , 2004, Science.

[59]  S. Shenouda,et al.  MicroRNA function in cancer: oncogene or a tumor suppressor? , 2009, Cancer and Metastasis Reviews.

[60]  N. Wingreen,et al.  The Small RNA Chaperone Hfq and Multiple Small RNAs Control Quorum Sensing in Vibrio harveyi and Vibrio cholerae , 2004, Cell.

[61]  W. Filipowicz,et al.  Repression of protein synthesis by miRNAs: how many mechanisms? , 2007, Trends in cell biology.

[62]  R. Grima,et al.  An effective rate equation approach to reaction kinetics in small volumes: theory and application to biochemical reactions in nonequilibrium steady-state conditions. , 2010, The Journal of chemical physics.

[63]  R. Lipowsky,et al.  Complex Degradation Processes Lead to Non-Exponential Decay Patterns and Age-Dependent Decay Rates of Messenger RNA , 2013, PloS one.

[64]  E. Izaurralde,et al.  Gene silencing by microRNAs: contributions of translational repression and mRNA decay , 2011, Nature Reviews Genetics.