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Biological Network Motifs - 2 Mahendra Piraveenan

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Page 1: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Biological Network

Motifs - 2

Mahendra Piraveenan

Page 2: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Topological Generalization of

network Motifs

Three node Sub graphs - 13

Four Node Sub graphs - 199

Five Node Sub graphs – Over 9000

Seven Node Subgraphs – Million

Fortunately , Most Biological Network shows families

of dominant motifs

Eg: Transcription Networks Show

Feed Forward Loops (FFL)

Dense Overlapping Regulons (DOR)

Single Input Modules (SIM)

Page 3: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Generalizing motifs – Role

replication

Page 4: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

First-In First-Out (FIFO) Program

Kxz1>Kxz2>Kxz3 K’xz1<K’xz2<K’xz3 Time

Kxz1

Kxz2

Kxz3

Kxz3

Kxz2

Kxz1

[X]

[Y]

[Z2]

[Z3]

[Z1]

Page 5: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

FIFO program

The FFL works as an FIFO program here

because of the OR functions at Zi

Notice that threshold levels have to be

reversed for Y and Z

Page 6: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Aside: E Coli Flagella –

Technological wonder

Page 7: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

FIFO program is governed by a FFL

Page 8: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Multi-input FFL in Neuronal Networks

FLP ASH

AVD

AVA

Nose TouchNoxious Chemicals

Nose Touch

Backward movement

Page 9: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Dense Overlapping Regulon (DOR)

Page 10: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

DORs

The Genes in each DOR have a shared

Global function

Such as stress response

Nutrient metabolism

Biosystehsis of key classes of celular components

The DOR forms the back bone of networks

global structure

So Can we use motifs to simplify networks?

Page 11: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

How do Network Motifs Integrate?

The E.coli Transcription Network (partial)

A single DOR Layer

FFLs and SIMs are integrated within DORs

A Master Regulators Layer

(lots of Auto-Reg.)Where are the XYZ

?

Page 12: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Compare with…

Page 13: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

DORs in transcription

networks

Form single layers - do not form cascades

No ‘Single line’ cascades

Rate limited networks tend not to employ such

cascades

Cascades are found in networks with interactions

that are rapid compared to the timescale in which

the network needs to function.

Page 14: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Network Motifs in developmental

transcription networks

These are not rate limited

Page 15: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Developmental Transcription Netwroks

The TF expression profile in a

developing Drosophila embryo

Page 16: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Developmental Transcription Netwroks

X Y X Y

•Both X AND Y are ON at the

same time.

•Genes regulated by X and Y

belong to the same tissue (or

strip).

•X OR Y is ON at a given time.

•Genes regulated by X and Y

belong to different tissues

(strips).

Two-node Feedback Loops - Locking

Page 17: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Developmental Transcription Netwroks

X Y

Z

X Y

Z

X Y

Z

X Y

Z

Regulating Feedback Loops

Regulated Feedback Loops

Do

ub

le P

osi

tive

Lo

op

s

Do

ub

le N

eg

ative

Lo

op

s

Page 18: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Developmental Transcription Netwroks

Regulated Feedback Loops as a Memory Element

Page 19: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Developmental Transcription Netwroks

Cascades

Time

[X]

[Y]

[Z]

Time

[X]

[Y]

[Z]

X Y Z X Y Z

Page 20: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Feed Back Loops in developmental transcription networks

X Y

Z

(Fast) Protein-Protein Interactions

(Slow) Transcriptional Interactions

•Z transcriptionally activates X and Y

•X forms a complex with Y.

•X phosphorylates Y.

Y

X

•X transcriptionally activates X.

•Y inhibits X.

Power Heater

Thermostat

Temperature-

Page 21: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Feed Back Loops Produce Oscillation (remember from Control theory?)

Mutation of the Drosophila CWO geneCdc20 oscillator controls Cell Cycle

Page 22: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Feedback Control

Page 23: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Cell Signaling networks

What are cell signaling networks?

Page 24: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Signal Transduction Cascades

X X P

Y Y P

Z Z P

T

T*

Page 25: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Popular Motifs in Signal Transduction

Cascades

X1 X2

Y1 Y2

Generalization of DOR

BiFan

Y2

Z

Y1

Diamond

X1 X2

Y1 Y2

Z

Y1 Y2

Z1 Z2

X

Y1 Y2

Z1 Z2

X1 X2

Multi-layer

Perceptrons

(multi-DORs)

X

Page 26: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

X1 X1 P

Y1 Y1 P

Z1 Z1 P

X2 X2 P

Y2 Y2 P

Z2 Z2 P

Multi Layer Perceptorns in Signal

Transduction Cascades

Page 27: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Dynamics of Signal Transduction

Cascades

)( 2211 XwXwfY

Yp

poo YYXvYXvdt

dY 2211

0dt

dY

At Steady State

/11 vw /22 vw ,

12211 XwXw Activation Threshold

Y

X1 X2

7.01 w7.02 w

X1

X2

0.5

0.5

Page 28: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Dynamics of Signal Transduction

Cascades

Y

X1 X2

7.01 w7.02 w

X1

X2

0.5

0.5

“AND” gate

Y

X1 X2

21 w22 w

X1

X2

0.5

0.5

“OR” gate

Page 29: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Dynamics of Signal Transduction

Cascades

)( 211 YwYwfZ

Zzz

p

X1 X2

Y1 Y2

Z

0.7 0.71.5 1.5

2 2

X1 X2

Y1 Y2

Z

0.7 0.71.5 1.5

0.6 0.6

“AND” gate

“OR” gate

Y1 Y2 Z

Y1 Y2 Z

Page 30: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Dynamics of Signal Transduction

Cascades

X1 X2

Y1 Y2

Z

0.7 0.71.5 1.5

2 -3

X1 X2

Y1 Y2

Z

1.7 0.71.7 0.7

2 -3

Y1 Y2 Z

Y2

ZY1 Z

Page 31: Biological Network Motifs - 2nisansa/Classes/02_University...2] [Z 3] [Z 1] FIFO program The FFL works as an FIFO program here because of the OR functions at Z i Notice that threshold

Summary

Network motifs can function in several biological processes (sensory systems,

development).

different time scales (milliseconds, cell generations).

Network motifs can produce temporal programs (LIFO, FIFO, oscillation).

Motifs within a network may be arranged in organized structures (perceptrons, interlocking FFL).

It is possible to understand network topology better by reducing the network to motif - topology


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