Skip to main content
SpringerLink
Log in

Network motifs that recur across species, including gene regulatory and protein–protein interaction networks

  • Review Article
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Cellular molecules interact in complex ways, giving rise to a cell’s functional outcomes. Conscientious efforts have been made in recent years to better characterize these patterns of interactions. It has been learned that many of these interactions can be represented abstractly as a network and within a network there in many instances are network motifs. Network motifs are subgraphs that are statistically overrepresented within networks. To date, specific network motifs have been experimentally identified across various species and also within specific, intracellular networks; however, motifs that recur across species and major network types have not been systematically characterized. We reason that recurring network motifs could potentially have important implications and applications for toxicology and, in particular, toxicity testing. Therefore, the goal of this study was to determine the set of intracellular, network motifs found to recur across species of both gene regulatory and protein–protein interaction networks. We report the recurrence of 13 intracellular, network motifs across species. Ten recurring motifs were found across both protein–protein interaction networks and gene regulatory networks. The significant pair motif was found to recur only in gene regulatory networks. The diamond and one-way cycle reversible step motifs were found to recur only in protein–protein interaction networks. This study is the first formal review of recurring, intracellular network motifs across species. Within toxicology, combining our understanding of recurring motifs with mechanism and mode of action knowledge could result in more robust and efficient toxicity testing models. We are sure that our results will support research in applying network motifs to toxicity testing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Notes

  1. Herein, called ‘motifs’ for brevity.

  2. NF-E2-related factor 2.

  3. Mitogen-activated protein kinase.

References

  • Albert R, Barabasi AL (2002) Statistical mechanics of complex networks. Rev Mod Phys 74:47–97

    Article  Google Scholar 

  • Alon U (2007a) An introduction to systems biology: design principles of biological circuits. Taylor and Francis, Boca Raton

    Google Scholar 

  • Alon U (2007b) Network motifs: theory and experimental approaches. Nat Genet 8:450–461

    Article  CAS  Google Scholar 

  • Barabasi AL, Albert R (1999) Emergence of scaling in random networks. Science 286:509–512

    Article  PubMed  Google Scholar 

  • Barabasi AL, Oltvai ZN (2004) Network biology: understanding the cell’s functional organization. Nat Genet 5:101–113

    Article  CAS  Google Scholar 

  • Davidson EH, Rast JP, Oliveri P, Ransick A, Calestani C, Yuh CH, Minokawa T, Amore G, Hinman V, Arenas-Mena C, Otim O, Brown CT, Livi CB, Lee PY, Revilla R, Rust AG, Pan ZJ, Schilstra MJ, Clarke PJC, Arnone MI, Rowen L, Cameron RA, McClay DR, Hood L, Bolouri H (2002) A genomic regulatory network for development. Science 295(5560):1669–1678

    Article  CAS  PubMed  Google Scholar 

  • Dorbin R, Beg QK, Barabasi AL, Oltvai ZN (2004) Aggregation of topological motifs in the Escherichia coli transcriptional regulatory network. BMC Bioinform 5

  • Duarte NC, Herrgård MJ, Palsson BØ (2004) Reconstruction and validation of Saccharomyces cerevisiae iND750, a fully compartmentalized genome-scale metabolic model. Genome Res 14:1298–1309

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Duarte NC, Becker SA, Jamshidi N, Thiele I, Mo ML, Vo TD, Srivas R, Palsson BØ (2007) Global reconstruction of the human metabolic network based on genomic and bibliomic data. Proc Natl Acad Sci 104(6):1777–1782

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Eom Y, Lee S, Jeong H (2006) Exploring local structural organization of metabolic networks using subgraph patterns. J Theor Biol 241:823–829

    Article  PubMed  Google Scholar 

  • Feist AM, Scholten JCM, Palsson BØ, Brockman FJ, Ideker T (2006) Modeling methanogenesis with a genome-scale metabolic reconstruction of Methanosarcina barkeri. Mol Syst Biol 2(2006):0004

    PubMed  Google Scholar 

  • Gavin AC, Bosche M, Krause R, Grandi P, Marzioch M, Bauer A, Schultz J, Rick JM, Michon AM, Cruciat CM et al (2002) Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415:141–147

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez O, Gronau S, Falb M, Pfeiffer F, Mendoza E, Zimmerb R, Oesterhelta D (2008) Reconstruction, modeling and analysis of Halobacterium salinarum R-1 metabolism. Mol BioSyst 4:148–159

    Article  CAS  PubMed  Google Scholar 

  • Guelzim N, Bottani S, Bourgine P, Képès F (2002) Topological and causal structure of the yeast transcriptional regulatory network. Nat Genet 31:60–63

    Article  CAS  PubMed  Google Scholar 

  • Halbeisen RE, Gerber AP (2009) Stress-dependent coordination of transcriptome and translatome in yeast. PLoS Biol 7(5):e1000105

    Article  PubMed Central  PubMed  Google Scholar 

  • Harbison CT, Gordon DB, Lee TI, Rinaldi NJ, Macisaac KD, Danford TW, Hannett NM, Tagne JB, Reynolds DB, Yoo J, Jennings EG, Zeitlinger J, Pokholok DK, Kellis M, Rolfe PA, Takusagawa KT, Lander ES, Gifford DK, Fraenkel E, Young RA (2004) Transcriptional regulatory code of a eukaryotic genome. Nature 431:99–104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ho Y, Gruhler A, Heilbut A, Bader GD, Moore L, Adams SL, Millar A, Taylor P, Bennett K, Boutilier K et al (2002) Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 415:180–183

    Article  CAS  PubMed  Google Scholar 

  • Hughes TR, Marton MJ, Jones AR, Roberts CJ, Stoughton R, Armour CD, Bennett HA, Coffey E, Dai H, He YD et al (2000) Functional discovery via a compendium of expression profiles. Cell 102:109–126

    Article  CAS  PubMed  Google Scholar 

  • Ingram PJ, Stumpf MPH, Stark J (2006) Network motifs: structure does not determine function. BMC Gen 7(108)

  • Ishii T, Yoshida K, Terai G, Fujita Y, Nakai K (2001) DBTBS: a database of Bacillus subtilis promoters and transcription factors. Nucl Acids Res 29(1):278–280

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Joshi A, van de Peer Y, Michoel T (2011) Structural and functional organization of RNA regulons in the post-transcriptional regulatory network of yeast. Nucl Acids Res 39(21):9108–9117

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kannen R, Tetali P, Vempala S (1997) Simple Markov-chain algorithms for generating bipartite graphs and tournaments. Random Struct Algorithms 14:293

    Google Scholar 

  • Kashani ZRM, Ahrabian H, Elahi E, Nowzari-Dalini A, Ansari ES, Asadi S, Mohammadi S, Schreiber F, Masoudi-Nejad A (2009) Kavosh: a new algorithm for finding network motifs. BMC Bioinform 10

  • Kashtan N, Itzkovitz S, Milo R, Alon U (2004) Efficient sampling algorithm for estimating subgraph concentrations and detecting network motifs. Bioinformatics 20(11):1745–1758

    Article  Google Scholar 

  • Kaveh A (2013) Introduction to graph theory and algebraic graph theory. In: Optimal analysis of structures by concepts of symmetry and regularity. Springer, New York

  • Kim W, Li M, Wang J, Pan Y (2011) Biological network motif detection and evaluation. BMC Syst Biol 5(Suppl 3):S5

  • Konagurthu AS, Lesk AM (2008a) On the origin of distribution patterns of motifs in biological networks. BMC Syst Biol 2(73)

  • Konagurthu AS, Lesk AM (2008b) Single and multiple input modules in regulatory networks. Proteins Struct Funct Bioinform 73(2):320–324

    Article  CAS  Google Scholar 

  • Kumar VS, Ferry JG, Marana CD (2011) Metabolic reconstruction of the archaeon methanogen Methanosarcina acetivorans. BMC Syst Biol 5:28

    Article  Google Scholar 

  • Lee TI, Rinaldi NJ, Robert F, Odom DT, Bar-Joseph Z, Gerber GK, Hannett NM, Harbison CT, Thompson CM, Simon I, Zeitlinger J, Jennings EG, Murray HL, Gordon DB, Ren B, Wyrick JJ, Tagne TB, Volkert TL, Reaenkel E, Gifford DK, Young RA (2002) Transcriptional regulatory networks in Saccharomyces cerevisiae. Science 298:799–804

    Article  CAS  PubMed  Google Scholar 

  • Lilienblum W, Dekant W, Foth H, Gebel T, Hengstler JG, Kahl R, Kramer PJ, Schweinfurth H, Wollin KM (2008) Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH). Arch Toxicol 82:211–223

    Article  CAS  PubMed  Google Scholar 

  • Luscombe NM, Babu MM, Yu H, Snyder M, Teichmann SA, Gerstein M (2004) Genomic analysis of regulatory network dynamics reveals large topological changes. Nature 431(7006):308–312

    Article  CAS  PubMed  Google Scholar 

  • Ma HW, Kumar B, Ditges U, Gunzer F, Buer J, Zeng AP (2004) An extended transcriptional regulatory network of Escherichia coli and analysis of its hierarchical structure and network motifs. Nucl Acids Res 32(22):6643–6649

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ma’ayan A, Jenkins SL, Neves S, Hasseldine A, Grace E, Dubin-Thaler B, Eungdamrong NJ, Weng G, Ram PT, Rice JJ, Keshenbaum A, Stolovitzky GA, Blitzer RD, Lyengar R (2005) Formation of regulatory patterns during signal propagation in a mammalian cellular network. Science 309:1078–1083

    Article  PubMed Central  PubMed  Google Scholar 

  • Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA (2002) Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62:638–646

    Article  CAS  PubMed  Google Scholar 

  • Mantus E, Obernier J, Crossgrove R, Grossblatt N, Karalic-Loncarevic M, Crago J (2007) Toxicity testing in the 21st century; a vision and a strategy. The National Academies Press, Washington, DC

    Google Scholar 

  • Martinez NJ, Ow MC, Barrasa IM, Hammell M, Sequerra R, Doucette-Stamm L, Roth FP, Ambros VR, Walhout AJM (2008) A C. elegans genome-scale microRNA network contains composite feedback motifs with high flux capacity. Genes Dev 22:2535–2549

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maslov S, Sneppen K (2002) Specificity and stability in topology of protein networks. Science 296:910–913

    Article  CAS  PubMed  Google Scholar 

  • Mazurie A, Bottani S, Vergassola M (2005) An evolutionary and functional assessment of regulatory network motifs. Genome Biol 6(4)

  • Milo R, Shen-Orr S, Itzkovitz S, Kashtan N, Chklovskii D, Alon U (2002) Network motifs: simple building blocks of complex networks. Science 298(5594):824–827

    Article  CAS  PubMed  Google Scholar 

  • Milo R, Itzkovitz S, Kashtan N, Levitt R, Shen-Orr S, Ayzenshtat I, Sheffer M, Alon U (2004) Superfamilies of evolved and designed networks. Science 303:1538–1542

    Article  CAS  PubMed  Google Scholar 

  • Moore JT, Moore LB, Maglich JM, Kliewer SA (2003) Functional and structural comparison of PXR and CAR. Biochim Biophys Acta 1619:235–238

    Google Scholar 

  • Newmann MEJ, Strogatz SH, Watts DJ (2001) Random graphs with arbitrary degree distributions and their applications. Phys Rev E 64:026118-1–026118-17

  • Nikitin A, Sergei E, Nikolai D, Ilya M (2003) Pathway studio—the analysis and navigation of molecular networks. Bioinformatics 19(16):2155–2157

    Article  CAS  PubMed  Google Scholar 

  • Park Y, Newmann MEJ (2003) Origin of degree correlations in the Internet and other networks. Phys Rev E 68:026112-1–026112-7

  • Ren B, Robert F, Wyrick JJ, Aparicio O, Jennings EG, Simon I, Zeitlinger J, Schreiber J, Hannett N, Kanin E, Volkert TL, Wilson CJ, Bell SP, Young RA (2000) Genome-wide location and function of DNA binding proteins. Science 290:2306–2309

    Article  CAS  PubMed  Google Scholar 

  • Ryall KA, Holland DO, Delaney KA, Kraeutler MJ, Parker AJ, Saucerman JJ (2012) Network reconstruction and systems analysis of cardiac myocyte hypertrophy signaling. J Biol Chem 287:42259–42268

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schwöbbermeyer H (2008) Network motifs. In: Junker B, Schreiber F (eds) Analysis of biological networks. Wiley, Hoboken

    Google Scholar 

  • Shah I, Houck K, Judson RS, Kavloch RJ, Martin MT, Reif DM, Wambaugh J, Dix DJ (2011) Using nuclear receptor activity to stratify hepatocarcinogens. PLOS One 6(2):e14584

  • Shalgi R, Lieber D, Oren M, Pilpel Y (2007) Global and local architecture of the mammalian microRNA-transcription factor regulatory network. PLoS Comput Biol 3(7):1291–1304

    Article  CAS  Google Scholar 

  • Shellman ER, Burant CF, Schnell S (2013) Network motifs provide signatures that characterize metabolism. Mol BioSyst 9:352–360

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shen-Orr SS, Milo R, Mangan S, Alon U (2002) Network motifs in the transcriptional regulation network of Escherichia coli. Nat Genet 31:64–68

    Article  CAS  PubMed  Google Scholar 

  • Shoval O, Alon U (2010) SnapShot: network motifs. Cell 143:326–326e1

    Article  PubMed  Google Scholar 

  • Shreiber F, Schwöbbermeyer H (2005) Frequency concepts and pattern detection for the analysis of motifs in networks. Trans Comput Syst Biol 3:89–104

    Google Scholar 

  • Sigurdsson MI, Jamshidi N, Steingrimsson E, Thiele I, Palsson BØ (2010) A detailed genome-wide reconstruction of mouse metabolism based on human Recon 1. BMC Syst Biol 4:140

    Article  PubMed Central  PubMed  Google Scholar 

  • Simon I, Barnett J, Hannett N, Harbison CT, Rinaldi NJ, Volkert TL, Wyrick JJ, Zeitlinger J, Gifford DK, Jaakkola TS, Young RA (2001) Serial regulation of transcriptional regulators in the yeast cell cycle. Cell 106:697–708

    Article  CAS  PubMed  Google Scholar 

  • Takagi S, Nakajima M, Mohri T, Yokoi T (2008) Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytrochrome P450 3A4. J Biol Chem 283(15):9674–9680

    Article  CAS  PubMed  Google Scholar 

  • Tong AH, Lesage G, Bader GD, Ding H, Xu H, Xin X, Young J, Berriz GF, Brost RL, Chang M et al (2004) Global mapping of the yeast genetic interaction network. Science 303:808–813

    Article  CAS  PubMed  Google Scholar 

  • Ullmann JR (1976) An algorithm for subgraph isomorphism. J Assoc Comput Mach 23(1):31–42

    Article  Google Scholar 

  • Wernicke S, Rasche R (2006) FANMOD: a tool for fast network motif detection. Bioinformatics 22(9):1152–1153

    Article  CAS  PubMed  Google Scholar 

  • Wong E, Baur B, Quader S, Huang CH (2012) Biological network motif detection: principles and practice. Brief Bioinform 13(2):202–205

    Article  PubMed Central  PubMed  Google Scholar 

  • Yeger-Logem E, Sattath S, Kashtan N, Itzkovitz S, Milo R, Pinter RY, Alon U, Margalit H (2004) Network motifs in integrated cellular networks of transcription–regulation and protein–protein interaction. PNAS 101(16):5939

    Google Scholar 

  • Zhang LV, King OD, Wong SL, Goldberg DS, Tong AHY, Lesage G, Andrews B, Bussey H, Boone C, Roth FP (2005) Motifs, themes and thematic maps of an integrated Saccharomyces cerevisiae interaction network. J Biol 4(6)

Download references

Acknowledgments

Mary Fox, DrPH, Johns Hopkins Bloomberg School of Public Health; Michael Trush, PhD, Johns Hopkins Bloomberg School of Public Health; Louis Scarano, PhD, US Environmental Protection Agency.

Author information

Authors and Affiliations

  1. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Robert Borotkanics

  2. Division of Health Sciences Informatics, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Harold Lehmann

Authors
  1. Robert Borotkanics
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harold Lehmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Borotkanics.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Borotkanics, R., Lehmann, H. Network motifs that recur across species, including gene regulatory and protein–protein interaction networks. Arch Toxicol 89, 489–499 (2015). https://doi.org/10.1007/s00204-014-1274-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-014-1274-y

Keywords

Search

Navigation