Network motifs in integrated cellular networks of transcription-regulation and protein-protein interaction.

Genes and proteins generate molecular circuitry that enables the cell to process information and respond to stimuli. A major challenge is to identify characteristic patterns in this network of interactions that may shed light on basic cellular mechanisms. Previous studies have analyzed aspects of this network, concentrating on either transcription-regulation or protein-protein interactions. Here we search for composite network motifs: characteristic network patterns consisting of both transcription-regulation and protein-protein interactions that recur significantly more often than in random networks. To this end we developed algorithms for detecting motifs in networks with two or more types of interactions and applied them to an integrated data set of protein-protein interactions and transcription regulation in Saccharomyces cerevisiae. We found a two-protein mixed-feedback loop motif, five types of three-protein motifs exhibiting coregulation and complex formation, and many motifs involving four proteins. Virtually all four-protein motifs consisted of combinations of smaller motifs. This study presents a basic framework for detecting the building blocks of networks with multiple types of interactions.

[1]  S. Mangan,et al.  The coherent feedforward loop serves as a sign-sensitive delay element in transcription networks. , 2003, Journal of molecular biology.

[2]  Hanah Margalit,et al.  Detection of regulatory circuits by integrating the cellular networks of protein-protein interactions and transcription regulation. , 2003, Nucleic acids research.

[3]  S. Mangan,et al.  Structure and function of the feed-forward loop network motif , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[4]  L. Mirny,et al.  Protein complexes and functional modules in molecular networks , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Z N Oltvai,et al.  Evolutionary conservation of motif constituents in the yeast protein interaction network , 2003, Nature Genetics.

[6]  Uri Alon,et al.  Response delays and the structure of transcription networks. , 2003, Journal of molecular biology.

[7]  U. Alon,et al.  Detailed map of a cis-regulatory input function , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  D. Bu,et al.  Topological structure analysis of the protein-protein interaction network in budding yeast. , 2003, Nucleic acids research.

[9]  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.

[10]  Shmuel Sattath,et al.  How reliable are experimental protein-protein interaction data? , 2003, Journal of molecular biology.

[11]  Katherine C. Chen,et al.  Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. , 2003, Current opinion in cell biology.

[12]  Alexander Rives,et al.  Modular organization of cellular networks , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[13]  U. Alon,et al.  Negative autoregulation speeds the response times of transcription networks. , 2002, Journal of molecular biology.

[14]  S. Shen-Orr,et al.  Network motifs: simple building blocks of complex networks. , 2002, Science.

[15]  A. Kimura,et al.  Chromosomal gradient of histone acetylation established by Sas2p and Sir2p functions as a shield against gene silencing , 2002, Nature Genetics.

[16]  Yaniv Ziv,et al.  Revealing modular organization in the yeast transcriptional network , 2002, Nature Genetics.

[17]  U. Alon,et al.  Assigning numbers to the arrows: Parameterizing a gene regulation network by using accurate expression kinetics , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  K. Sneppen,et al.  Specificity and Stability in Topology of Protein Networks , 2002, Science.

[19]  P. Kemmeren,et al.  Protein interaction verification and functional annotation by integrated analysis of genome-scale data. , 2002, Molecular cell.

[20]  P. Bourgine,et al.  Topological and causal structure of the yeast transcriptional regulatory network , 2002, Nature Genetics.

[21]  S. Shen-Orr,et al.  Network motifs in the transcriptional regulation network of Escherichia coli , 2002, Nature Genetics.

[22]  J. Ferrell.  Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. , 2002, Current opinion in cell biology.

[23]  Nicola J. Rinaldi,et al.  Serial Regulation of Transcriptional Regulators in the Yeast Cell Cycle , 2001, Cell.

[24]  A. Grigoriev.  A relationship between gene expression and protein interactions on the proteome scale: analysis of the bacteriophage T7 and the yeast Saccharomyces cerevisiae. , 2001, Nucleic acids research.

[25]  A. Barabasi,et al.  Lethality and centrality in protein networks , 2001, Nature.

[26]  R. Ozawa,et al.  A comprehensive two-hybrid analysis to explore the yeast protein interactome , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  D. Botstein,et al.  Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF , 2001, Nature.

[28]  H. McAdams,et al.  Global analysis of the genetic network controlling a bacterial cell cycle. , 2000, Science.

[29]  J. Levine,et al.  Surfing the p53 network , 2000, Nature.

[30]  D. Fell,et al.  The small world of metabolism , 2000, Nature Biotechnology.

[31]  M. Newman,et al.  Random graphs with arbitrary degree distributions and their applications. , 2000, Physical review. E, Statistical, nonlinear, and soft matter physics.

[32]  P D Karp,et al.  Global properties of the metabolic map of Escherichia coli. , 2000, Genome research.

[33]  James R. Knight,et al.  A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae , 2000, Nature.

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

[35]  Michael Q. Zhang,et al.  SCPD: a promoter database of the yeast Saccharomyces cerevisiae , 1999, Bioinform..

[36]  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.

[37]  E. Davidson,et al.  Genomic cis-regulatory logic: experimental and computational analysis of a sea urchin gene. , 1998, Science.

[38]  D. Lohr,et al.  Transcriptional regulation in the yeast GAL gene family: a complex genetic network , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  C. Gross,et al.  DnaK, DnaJ, and GrpE heat shock proteins negatively regulate heat shock gene expression by controlling the synthesis and stability of sigma 32. , 1990, Genes & development.

[40]  Adam J. Smith,et al.  The Database of Interacting Proteins: 2004 update , 2004, Nucleic Acids Res..

[41]  Nicola J. Rinaldi,et al.  Supporting online material for : Transcriptional Regulatory Networks in Saccharomyces cerevisiae , 2002 .

[42]  Marek S. Skrzypek,et al.  YPDTM, PombePDTM and WormPDTM: model organism volumes of the BioKnowledgeTM Library, an integrated resource for protein information , 2001, Nucleic Acids Res..

[43]  Gary D Bader,et al.  BIND--The Biomolecular Interaction Network Database. , 2001, Nucleic acids research.

[44]  M. Santoro,et al.  Heat shock factors and the control of the stress response. , 2000, Biochemical pharmacology.

[45]  Dmitrij Frishman,et al.  MIPS: a database for genomes and protein sequences , 1999, Nucleic Acids Res..

[46]  A. Hoffmann,et al.  The I (cid:1) B –NF-(cid:1) B Signaling Module: Temporal Control and Selective Gene Activation , 2022 .