Introduction

Cells encounter different situations that require

different proteins.

The cell continuously monitors its environment

and calculates the amount at which each type of
protein is needed.

This information-processing function, which

determines the rate of production of each protein,
is largely carried out by transcription networks.
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Transcription factor
A transcription factor (TF) is a protein that binds
to the promoter region of its target gene and
controls the expression (transcription) of the
target gene.

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The cognitive problem of the cell
To represent the different environmental states, the cell
uses special proteins called transcription factors as
symbols.

Transcription factors are usually designed to transit

rapidly between active and inactive molecular states, at
a rate that is modulated by a specific environmental
signal (input).

The bacterium E. coli has an internal representation with

about 300 degrees of freedom (transcription factors) and
these regulate the rates of production of ~4000 proteins.

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E. coli a model organism

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The mapping between environmental signals, transcription
factors inside the cell, and the genes that they regulate

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Elements of transcription networks
Gene transcription regulation, the basic picture

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Transcription factors --- activators and repressors
activator

repressor

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Activators increase gene production

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Repressors decrease gene production

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Transcription networks
In the network, nodes are genes and edges
represent transcriptional regulation of one gene
by the protein product of another gene.

A directed edge X Y means that the product

of gene X is a transcription factor protein that
binds the promoter of gene Y to control the rate
at which gene Y is transcribed.

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Backtracking to find active sub-network

Define differentially expressed genes

Identify TFs that regulate these genes

Identify further TFs that regulate these TFs

Active regulatory sub-network

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A transcription network that represents about 20% of
the transcription interactions in the bacterium E. coli

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Ref: Shen-Orr SS, Milo R, Mangan S, Alon U. Network motifs in the transcriptional regulation network of Escherichia coli. 2002. Nat Genet.2 31(1):64-8.
Separation of timescales
The input signals usually change transcription factor
activities on a sub-second timescale. Binding of the
active transcription factor to its DNA sites often reaches
equilibrium in seconds.

Transcription and translation of the target gene takes

minutes, and the accumulation of the protein product can
take minutes to hours

The transcription factor activity levels can be considered

to be at steady state within the equations that describe
network dynamics on the slow time scale of changes in
protein levels.

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Timescales for the reactions in the transcription
network of bacterium E. coli

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Input function
The strength of the effect of a transcription factor on the
transcription rate of its target genes is described by an
input function.

When X regulates Y, represented in the network by

X Y, the number of molecules of protein Y produced
per unit time is a function of the concentration of X in its
active form X*
rate of production Y = f(X*)

Typically, the input function is a monotonic, S-shaped

function. It is a increasing function when X is an activator
and a decreasing function when X is a repressor.

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Input function --- Hill function
X *n
f (X *) Hill function for activator
K Xn *n

: maximal expression level of the promoter; K: activation coefficient

n: Hill coefficient n governs the steepness of the input function
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Input function --- Hill function

f (X *) *
Hill input function for repressor
X n
1 ( )
K

K: repression coefficient 17
Logic input function: a simple framework for
understanding network dynamics
For mathematical clarity, it is often useful to use even
simpler functions that capture the essential behavior of
these input function.

Logic approximation: in this approximation, the gene is

either OFF, f(X*) = 0, or maximally ON, f(X*) = . The
threshold for activation is K.

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Logic approximation for activator
f ( X * ) ( X * K ) logic approximation for activator

where (step-function) is equal to 0 or 1 according to the logic statement

in the parentheses. The logic approximation is equivalent to a very steep
Hill function with Hill coefficient n .
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Logic approximation for repressor
f ( X * ) ( X * K ) logic approximation for repressor

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Multi-dimensional input functions govern genes with several inputs

f ( X * , Y * ) x X * yY *

f ( X * ,Y * ) ( X * K x ) (Y * K y ) ~ X * AND Y *

f ( X * , Y * ) ( X * K x OR Y * K y ) ~ X * OR Y *

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Interim summary
Input function: the rate of production of gene
product Y is a function of the concentration of
active transcription factor X*

The input functions are often rather sharp and

can be approximated by Hill functions or logic
gates.

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Dynamics and response time of simple gene
regulation
X Y : transcription factor X regulates gene Y.

The cell produces protein Y at a constant rate, which we will denote

(units of concentration per unit time).

The degradation rate (deg , its specific destruction by specialized

proteins in the cell) and the dilution (dil , the reduction in
concentration due to the increase of cell volume during growth),
giving a total degradation/dilution rate (in units of 1/time) of =deg
+ deg

The change in the concentration of Y is due to the difference

between its production and degradation/dilution, as described by a
dynamic equation
dY/dt = -Y (2.4.2)

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Response time
The response time, T1/2 , is generally
defined as the time to reach halfway
between the initial and final levels in a
dynamic process.

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Decay of protein concentration following a
sudden drop in production rate
At steady state, Y reaches a constant concentration Yst =
/
What happens if we take away the input signal, so that
production of Y stops (=0)? The solution of Equation
(2.4.2) with =0 is an exponential decay of Y
concentration: Y(t) = Yste-t (2.4.4)

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Rise in protein concentration following a
sudden increase in production rate
dY/dt = -Y and Y(0)=0 Y(t) = Yst (1 - e-t)
At early times, Yt when t << 1

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References
An Introduction to Systems Biology:
Design Principles of Biological Circuits.
2006. Uri Alon.
Transcription Factors. 2001.J. Locker.

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