COMPLEX NETWORKS OF BIOMOLECULAR INTERACTIONS Franois Kps - - PowerPoint PPT Presentation

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 ...

Protein 1 Protein 2 Protein 3 Protein 11 Protein 10 Protein 9 Protein 8 Protein 7 Protein 6 Protein 5 Protein 4 Protein 12

0,8 0,4 0,1 0,2 1,0 0,2 0,1 0,8 0,9 0,8 0,5 0,5 0,2 0,5 0,3 0,3

Interactions between proteins

Interactions between enzymes and metabolites

Michaelis-Menten Law

• 1/Km

1/Vmax

1/[S]T 1/V 1/V = 1/Vmax + Km/Vmax . 1/[S]T Lineweaver-Burk Equation

Interactions between enzymes and metabolites

Metabolome

Interactions between enzymes and metabolites

DNA mRNA Protein Active Protein

SEQUENCES Regulatory Coding TRANSCRIPTION TRANSLATION FOLDING

Interactions between regulatory proteins and DNA regulatory regions

Interactions between regulatory proteins and DNA regulatory regions

• +
• Gene A

Gene E Gene D Gene C Gene B

RR ORF

Interactions between regulatory proteins and DNA regulatory regions

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

A Région régulatoire Gène rapporteur

ADN

Activation transcriptionnelle

Initiateur de transcription Domaine d'activation Domaine de liaison

B

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

• +
• Gene A

Gene E Gene D Gene C Gene B

RR ORF

Interactions between regulatory proteins and DNA regulatory regions

SEVERAL SEVERAL GENES GENES SEVERAL SEVERAL GENES GENES

YLR176C YAL021C YOL051W YGL035C YBR049C YMR280C YPL248C YHR119W YKL109W YNL216W YCR084C 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

A A NETWORK NETWORK OF OF GENES GENES A A NETWORK NETWORK OF OF GENES GENES

Pleiotropic or multigenic regulation ? MODELING MODELING A A GENETIC GENETIC NETWORK NETWORK MODELING MODELING A A GENETIC GENETIC NETWORK NETWORK

1 10 100 2 4 6 8 10 12 14

Regulated genes Regulating proteins

Indegree

Y = M0*e

M1*X

156,59 M0

• 0,44525

M1 0,98574 R

Global Topology INDEGREE INDEGREE DISTRIBUTION DISTRIBUTION INDEGREE INDEGREE DISTRIBUTION DISTRIBUTION

1 10 1 10

Regulating proteins Regulated genes

Outdegree

Y = M0*X

M1

22,765 M0

• 0,86409

M1 0,94621 R

Global Topology OUTDEGREE OUTDEGREE DISTRIBUTION DISTRIBUTION OUTDEGREE OUTDEGREE DISTRIBUTION DISTRIBUTION

Global Topology JOINT JOINT IN IN / / OUT OUT DISTRIBUTION DISTRIBUTION JOINT JOINT IN IN / / OUT OUT DISTRIBUTION DISTRIBUTION

ORF Direct descent Overall descent YBR049C 18 86 YMR043W 29 52 YNL216W 9 49 YGL207W 11 22 YGL073W 12 12 YML010W 1 2 ESSENTIALITY ESSENTIALITY AND AND DESCENT DESCENT SIZE SIZE ESSENTIALITY ESSENTIALITY AND AND DESCENT DESCENT SIZE SIZE

Lethal gene inactivation ESSENTIAL ESSENTIAL INTER-REGULATORY INTER-REGULATORY GENES GENES ESSENTIAL ESSENTIAL INTER-REGULATORY INTER-REGULATORY GENES GENES

Local Structure of the Network of Interactions

A B C D A B C D A B C D UNIFORM SMALL WORLD HIGHLY CLUSTERED FRAGMENTED Local topology LOCAL LOCAL APPORTIONMENT APPORTIONMENT OF OF EDGES EDGES PER PER VERTEX VERTEX LOCAL LOCAL APPORTIONMENT APPORTIONMENT OF OF EDGES EDGES PER PER VERTEX VERTEX

Local topology

R a b c e f 1 0.5 R a b c e f R a b c e f

CLIQUISHNESS CLIQUISHNESS (clustering (clustering coefficient) coefficient) CLIQUISHNESS CLIQUISHNESS (clustering (clustering coefficient) coefficient)

Dynamics and Modularity

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

FEEDBACK CIRCUITS

MOTIFS MOTIFS MOTIFS MOTIFS

POSITIVE Even Multistationarity Differentiation NEGATIVE Odd Homeostasis Stable regulation SIGN # negative interactions Dynamic property Biological property Topology Qualitative dynamics (in vivo and numerical simulations carried

• ut)

MODULES Out (A)

A A B

Positive circuits

Sporulation MDR Pseudo-hyph

FEEDBACK FEEDBACK CIRCUITS CIRCUITS AMONG AMONG INTERREGULATORY INTERREGULATORY GENES GENES FEEDBACK FEEDBACK CIRCUITS CIRCUITS AMONG AMONG INTERREGULATORY INTERREGULATORY GENES GENES

DNA damage

Negative circuits

Glc absence

• xygen

FEEDBACK FEEDBACK CIRCUITS CIRCUITS AMONG AMONG INTERREGULATORY INTERREGULATORY GENES GENES FEEDBACK FEEDBACK CIRCUITS CIRCUITS AMONG AMONG INTERREGULATORY INTERREGULATORY GENES GENES

FEEDBACK CIRCUITS

MOTIFS MOTIFS MOTIFS MOTIFS

NEGATIVE Odd Oscillator Stable regulation

• r oscillation

TYPE # negative interactions Dynamic property Biological property Topology Qualitative dynamics (in vivo and numerical simulations carried

• ut)

A B C

MODULES

TRIANGLES (Feed-forward loops)

MOTIFS MOTIFS MOTIFS MOTIFS

COHERENT

Filter out pulses Respond to persistent stimulations Rapidly shutdown Decide from fluctuating signal

A B C A B C

INCOHERENT

Initially reacts strongly Later comes back to intermediate levels Easily reverse

In (A) Out (C) TYPE Dynamic property Biological property Topology Qualitative dynamics (Coherent triangle was numerically simulated) MODULES

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.

Incoherent Incoherent Triangles Triangles Incoherent Incoherent Triangles Triangles

CASCADES (Linear set of regulations)

MOTIFS MOTIFS MOTIFS MOTIFS

SHORT

Rapidly shoots up Fast response in microbe

A Z

Time -> LONG

Long lag before it shoots up Time counting in multicellular

In (A) Out (Z)

A B Z

... TYPE Dynamic property Biological property Topology Qualitative dynamics (Not simulated yet) MODULES

Cascades Cascades Cascades Cascades

Combination of long cascade and positive circuits

MOTIFS MOTIFS MOTIFS MOTIFS

LOCK-ON

Ratchet Succession of time lags and differentiation events in multicellular development

A B

...

C D E F X Y Z

In (A) Out (C) TYPE Dynamic property Biological property Topology Qualitative dynamics for a single-colored series (Not simulated yet) MODULES

SIM / SOM

MOTIFS MOTIFS MOTIFS MOTIFS

Ordered temporal response Sequential firing based

• n differential thresholds

B A D A B C

In (A) Out (C) Single-Input Module TYPE Dynamic property Biological property Topology Qualitative dynamics (Verified in vivo) MODULES

C

Out (B)

' AND ' logical gate Co-regulation

Single-Output Module

D

In (A) Out (D) In (B)

MOTIFS MOTIFS OF OF MOTIFS MOTIFS MOTIFS MOTIFS OF OF MOTIFS MOTIFS

Is it possible to spot combinations of motifs ? What could be said about their representation ? What could be said about their topology ? What could be said about their dynamics ?

1) 1) Recompose Recompose motifs motifs in in a a useful useful way way 2) 2) Top-down Top-down partition partition into into 'functional' 'functional' modules modules 3) 3) Go Go into into more more global global dynamics dynamics 4) 4) Analyze Analyze mixed mixed networks networks 5) 5) Realistically Realistically model model evolution evolution of

• f networks

networks 6) 6) Unfold Unfold topologies topologies in in geometrical geometrical cellular cellular space space 7) 7) Control Control 8) 8) Exploit Exploit hybrid hybrid formalisms formalisms Some Some of

• f the

the present present challenges challenges Some Some of

• f the

the present present challenges challenges

a) a) To To hold hold the the pipettes pipettes b) b) To To cope cope with with the the massive massive amount amount of

• f data

data c) c) To To cope cope with with the the lack lack of

• f data

data d) d) No No opinion

• pinion

For For which which purpose purpose do do we we need need non-biologists non-biologists in in Biology Biology ? For For which which purpose purpose do do we we need need non-biologists non-biologists in in Biology Biology ?