COMPLEX NETWORKS OF BIOMOLECULAR INTERACTIONS François Képès Francois.Kepes@genopole.cnrs.fr
CONTENT - Interacting partners and their interaction - Methods to obtain a network of interactions - Global structure of the network of interactions - Local structure - Dynamics and Modularity - Spatial aspects
Interacting partners and their interaction
PROTEIN / PROTEIN Interactions between proteins Proteomics METABOLISM Interactions between enzymes and metabolites Metabolomics PROTEIN / DNA Interactions between regulatory proteins and DNA regulatory regions Transcriptomics OTHERS ...
Interactions between proteins Protein 6 0,3 Protein 5 Protein 12 0,5 Protein 11 1,0 0,8 0,2 0,1 0,2 Protein 1 Protein 2 Protein 4 Protein 10 0,2 0,8 0,1 0,5 0,8 0,3 0,4 0,9 Protein 9 Protein 8 Protein 3 0,5 Protein 7
Interactions between enzymes and metabolites
Interactions between enzymes and metabolites Michaelis-Menten Law 1/V 1/Vmax -1/Km 0 1/[S] T 1/V = 1/Vmax + Km/Vmax . 1/[S] T Lineweaver-Burk Equation
Interactions between enzymes and metabolites Metabolome
Interactions between regulatory proteins and DNA regulatory regions SEQUENCES Regulatory Coding DNA TRANSCRIPTION mRNA TRANSLATION Protein FOLDING Active Protein
Interactions between regulatory proteins and DNA regulatory regions
Interactions between regulatory proteins and DNA regulatory regions Gene B Gene A - Gene D RR ORF Gene C + - - Gene E
PROTEIN / PROTEIN Interactions between proteins Proteomics METABOLISM Interactions between enzymes and metabolites Metabolomics PROTEIN / DNA Interactions between regulatory proteins and DNA regulatory regions Transcriptomics
A A MIXED MIXED NETWORK NETWORK A A MIXED MIXED NETWORK NETWORK
Information Flux in Biology Epigenesis
Methods to obtain a network of interactions (Post-genomics)
Proteomics Separation, identification and quantification of proteins
Proteomics Intracellular Localization
Proteomics Double-hybrid approaches Initiateur de Domaine transcription d'activation B A Domaine Activation de transcriptionnelle liaison Gène rapporteur Région régulatoire ADN
Proteomics Protein Complexes Assessment Specific Antibody A B
Transcriptomics Complementary DNA Microarrays
Transcriptomics Oligonucleotide Biochip
Transcriptomics Other techniques : RT-PCR SAGE
Transcriptomics Chromatin Immuno-Precipitation (ChIP)
Transcriptomics Bioinformatics Information content expressed in bits
Global Structure of the Network of Interactions
SEVERAL GENES SEVERAL GENES SEVERAL SEVERAL GENES GENES Interactions between regulatory proteins and DNA regulatory regions Gene B Gene A - Gene D RR ORF Gene C + - - Gene E
YLR176C YAL021C YOL051W A NETWORK A NETWORK OF OF GENES GENES A NETWORK A NETWORK OF OF GENES GENES YGL035C YBR049C YMR280C YPL248C YHR119W YKL109W YNL216W YLR176C YOL051W YBR049C YHR119W YGL035C YAL021C YMR280C YPL248C YKL109W YCR084C YHL027W YGL209W YBR112C YCR084C YFL031W YLR256W YNL216W YCL066W YHR084W YCR097W YGL207W YJL056C YMR043W YER111C YOL004W YLR182W YLR131C YCL067C YGR044C YBR083W YDR448W YER040W YGL013C YNL027W YDR176W YBL005W YJL110C YBL103C YKR034W YPR065W YPL016W YDR146C YDR123C YKL185W YJR094C YJR060W YML010W YEL009C YNL103W YBL008W YDR207C YIR017C YGL073W 166 72 76 43 10 YLR256W YHL027W YCL066W YFL031W YBR112C YHR084W YGL209W YBR083W YCR097W YER111C YMR043W YGR044C YLR131C YGL207W YOL004W YCL067C YJL056C YLR182W YGL013C YPR065W YBL005W YKL185W YNL027W YDR146C YJR094C YBL103C YDR448W YDR123C YJL110C YDR176W YPL016W YER040W YKR034W YGL073W YML010W YBL008W YDR207C YJR060W YIR017C YEL009C YNL103W 166 72 76 43 10
MODELING MODELING A A GENETIC GENETIC NETWORK NETWORK MODELING MODELING A A GENETIC GENETIC NETWORK NETWORK Pleiotropic or multigenic regulation ?
INDEGREE DISTRIBUTION INDEGREE DISTRIBUTION INDEGREE DISTRIBUTION INDEGREE DISTRIBUTION Global Topology Indegree 100 M1*X Y = M0*e Regulated genes M0 156,59 M1 -0,44525 R 0,98574 10 1 0 2 4 6 8 10 12 14 Regulating proteins
OUTDEGREE DISTRIBUTION OUTDEGREE DISTRIBUTION OUTDEGREE DISTRIBUTION OUTDEGREE DISTRIBUTION Global Topology Outdegree M1 Regulating proteins Y = M0*X M0 22,765 10 M1 -0,86409 R 0,94621 1 1 10 Regulated genes
JOINT IN JOINT IN / / OUT OUT DISTRIBUTION DISTRIBUTION JOINT JOINT IN IN / / OUT OUT DISTRIBUTION DISTRIBUTION Global Topology
ESSENTIALITY AND ESSENTIALITY AND DESCENT DESCENT SIZE SIZE ESSENTIALITY ESSENTIALITY AND AND DESCENT DESCENT SIZE SIZE ORF Direct descent Overall descent YBR049C 18 86 YMR043W 29 52 YNL216W 9 49 YGL207W 11 22 YGL073W 12 12 YML010W 1 2
ESSENTIAL INTER-REGULATORY ESSENTIAL INTER-REGULATORY GENES GENES ESSENTIAL ESSENTIAL INTER-REGULATORY INTER-REGULATORY GENES GENES Lethal gene inactivation
Local Structure of the Network of Interactions
LOCAL APPORTIONMENT LOCAL APPORTIONMENT OF OF EDGES EDGES PER PER VERTEX VERTEX LOCAL APPORTIONMENT LOCAL APPORTIONMENT OF OF EDGES EDGES PER PER VERTEX VERTEX Local topology A A A B C B C B C D D D UNIFORM SMALL WORLD HIGHLY CLUSTERED FRAGMENTED
CLIQUISHNESS (clustering CLIQUISHNESS (clustering coefficient) coefficient) CLIQUISHNESS CLIQUISHNESS (clustering (clustering coefficient) coefficient) Local topology b b b a a a R R R f f f c c c e e e 0 0.5 1
Dynamics and Modularity
MOTIFS MOTIFS MOTIFS MOTIFS Homogeneous networks: Why partition at all ? •Modularity •Dynamical explanation •Biological relevance •Compositionnality
MOTIFS MOTIFS MOTIFS MOTIFS Physical Qualitative Numerical In vivo Topology properties dynamics simulation simulation
MOTIFS MOTIFS MOTIFS MOTIFS MODULES FEEDBACK CIRCUITS SIGN POSITIVE NEGATIVE # negative interactions Even Odd Dynamic property Multistationarity Homeostasis Stable regulation Biological property Differentiation A A Topology B Qualitative dynamics Out (A) ( in vivo and numerical simulations carried out)
FEEDBACK FEEDBACK CIRCUITS CIRCUITS AMONG AMONG INTERREGULATORY INTERREGULATORY GENES GENES FEEDBACK FEEDBACK CIRCUITS CIRCUITS AMONG AMONG INTERREGULATORY INTERREGULATORY GENES GENES Sporulation MDR Pseudo-hyph Positive circuits
FEEDBACK FEEDBACK CIRCUITS CIRCUITS AMONG AMONG INTERREGULATORY INTERREGULATORY GENES GENES FEEDBACK FEEDBACK CIRCUITS CIRCUITS AMONG AMONG INTERREGULATORY INTERREGULATORY GENES GENES oxygen Glc absence DNA damage Negative circuits
MOTIFS MOTIFS MOTIFS MOTIFS MODULES FEEDBACK CIRCUITS TYPE NEGATIVE # negative interactions Odd Dynamic property Oscillator Stable regulation Biological property or oscillation B Topology A C Qualitative dynamics ( in vivo and numerical simulations carried out)
MOTIFS MOTIFS MOTIFS MOTIFS MODULES TRIANGLES (Feed-forward loops) COHERENT INCOHERENT TYPE Filter out pulses Initially reacts strongly Dynamic property Respond to persistent stimulations Later comes back Rapidly shutdown to intermediate levels Biological property Decide from fluctuating signal Easily reverse B B Topology A C A C In (A) Qualitative dynamics (Coherent triangle was Out (C) numerically simulated)
Incoherent Incoherent Triangles Triangles Incoherent Triangles Incoherent Triangles YGL209W: repressor involved in glucose repression . YGL035C: repressor involved in glucose repression. YDR146C: controls cell cycle-specific transcription. YKL109W: glucose-repressed subunit of the HAP transcriptional complex involved in the fermentation-respiration shift. YMR280C: required for derepression of gluconeogenic enzymes. YPL248C: involved in expression of galactose-induced genes.
MOTIFS MOTIFS MOTIFS MOTIFS MODULES CASCADES (Linear set of regulations) SHORT LONG TYPE Rapidly shoots up Long lag before it shoots up Dynamic property Time counting Biological property Fast response in microbe in multicellular Topology A Z ... A B Z In (A) Qualitative dynamics Time -> (Not simulated yet) Out (Z)
Cascades Cascades Cascades Cascades
MOTIFS MOTIFS MOTIFS MOTIFS MODULES Combination of long cascade and positive circuits LOCK-ON TYPE Ratchet Dynamic property Succession of time lags and differentiation events in Biological property multicellular development ... A B C F Z D E X Y Topology In (A) Qualitative dynamics for a single-colored series Out (C) (Not simulated yet)
MOTIFS MOTIFS MOTIFS MOTIFS MODULES SIM / SOM Single-Input Module Single-Output Module TYPE Dynamic property Ordered temporal ' AND ' logical gate response Biological property Sequential firing based Co-regulation on differential thresholds A B C A Topology B D C D In (A) In (A) Qualitative dynamics Out (B) In (B) (Verified in vivo ) Out (C) Out (D)
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