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NPTEL – Biotechnology- Systems Biology
Transcription Networks
Dr. M. Vijayalakshmi
School of Chemical and Biotechnology
SASTRA University
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NPTEL – Biotechnology- Systems Biology
Table of Contents
1 INTRODUCTION ............................................................................................... 3
1.1 TRANSCRIPTION NETWORK-ELEMENTS ............................................................ 3
1.2 TIMESCALES OF TRANSCRIPTION NETWORKS ................................................... 6
1.3 MODULARITY OF TRANSCRIPTION NETWORKS ................................................... 6
1.2 SIGNS ON THE EDGES .................................................................................... 7
1.2.1 Activation or Positive Control ................................................................ 7
1.2.2 Repression or Negative Control ........................................................... 8
2 REFERENCES .................................................................................................. 9
2.1 TEXT BOOK ................................................................................................... 9
2.2 LITERATURE REFERENCES .............................................................................. 9
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1 Introduction
The living cell is a complex machinery involving thousands of interacting proteins
and other biological molecules. These cells utilise proteins based on the
situations they encounter. During sugar sensing, the cells begin to secrete
proteins that transport sugar into the cells. Cells respond to damage by
producing damage repair proteins. Every cell thus senses its environment
continuously, regulates protein production and maintains cellular homeostasis.
Live cells as we know are kept dynamic through gene expression programs that
involve the transcription of thousands of genes in a coordinated manner. As we
all know, the expression of a gene is facilitated by transcription regulatory
proteins which recognize specific promoter sequences. The association of
regulatory proteins with genes across a genome and the continuous cascade of
information processing which senses
the rate of production of a particular
protein inside a cell constitute a transcription regulatory network. These are in
general called transcription networks. Metabolic networks describe the possible
pathways that a cell may use to accomplish metabolic processes. In a similar
way the map of the transcriptional regulatory network of an organism describes
potential pathways the cells of the organisms utilise to regulate global gene
expression programs. This network map establishes a high connectivity between
gene expression programs and cellular functions through networks of
transcriptional regulatory molecules which in turn regulate other molecular
players in transcription.
1.1 Transcription Network-Elements
We know that transcription networks depict the interaction between transcription
factors and genes. The process of transcription ensures that RNA polymerase
produces mRNA (messenger RNA) corresponding to the coding sequence of a
gene. The mRNA is translated to form a protein which is also referred to as the
gene product. Each gene is preceded by
a small stretch of regulatory DNA
called promoter. The promoter is a specific DNA sequence that can bind RNA
polymerase, which is a complex of several proteins. The rate at which the gene is
transcribed is determined by the quality of the binding site and the promoter
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which controls the number of mRNA produced per unit time. The RNA
polymerase complex acts on a number of genes while the transcription factors
regulate changes in expression profiles of specific genes. The transcription
factors when bound change the probability per unit time of RNA polymerase
binding to the promoter to produce the mRNA. Transcription factors can also
function as activators which increase the transcription rate of a gene or as
repressors which reduce the transcription rate. The transcription factor proteins
themselves are encoded by genes which are regulated by other transcription
factors. These transcription factors might have been regulated by other set of
transcription factors in the genome.
Such a complexity leads to a set of interactions which may be visualised to form
a transcription network. Thus a transcription network depicts all interactions of
the transcription regulatory proteins inside the cell. In such a network the genes
are represented by nodes and the edges represents the transcription regulation
of one gene by the protein product of the other. Therefore in a transcription
network
the directed edge XY means that the product of a gene X is a
transcription factor protein which controls the rate of transcription of gene Y (by
binding to the promoter of gene Y) , which is explained in the following Fig 1.
Fig 1 A schematic of transcription and translation of a
gene Y
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As shown in the Fig 2, the network has inputs called signals which represent
information from the environment.
A signal could be a protein modification,
environmental signal, biochemical stimuli, small molecule or a molecular partner
that influences one of the transcription factors in the network. The signals initiate
a physical change in the transcription factor protein and switch it to an active
molecular state. The signal SX therefore shifts the gene X to its active state X*,
binds to the promoter of the gene Y, increasing the rate of transcription and
hence increasing the production of protein Y. The gene network is thus a
dynamic system. With the arrival of the input signal S X gene activation profiles
change, activities of transcription factors change resulting in changes in protein
production rate.
Fig 2. A typical Transcription Network depicting the interaction between the
Signals, Transcription Factors and Genes
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1.2 Timescales of Transcription Networks
The timescales at which reactions happen in transcription network are quite
interesting to note. Table 1 explain timescales of reactions taking place in E. coli.
We can observe that the input signals such as biochemical stimuli or temperature
change the activity of transcription factors on sub second (milliseconds)
timescale. The binding of the active transcription factor to its DNA site attains
equilibrium in seconds. The transcription and translation of the target gene
happens in minutes while the accumulation if protein products and change in the
concentration of the stable protein takes hours.
Table 1 Timescales of reactions in the Transcription Network
of the Bacterium E. coli
Binding of a small molecule (a signal) to a
transcription factor, causing a change in
transcription factor activity
~1 ms
Binding of active transcription factor to its
DNA site
~1 sec
Transcription + Translation of the gene
~5 min
Timescale for 50% change in
concentration of the translated protein
(stable proteins)
~1 h (one cell generation)
1.3 Modularity of Transcription Networks
A remarkable property of transcription networks is the modularity of the
components of the network. This allows taking off the DNA of a gene from one
organism and expressing it on the other. The best example is the isolation of the
green fluorescent protein (GFP) from the genome of a jelly fish and to introduce
this gene into bacteria causing the bacteria to express green fluorescence.
This modularity confers plasticity to transcription networks during evolution,
facilitating introduction of newer genes and newer regulatory pathways. The
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edges in transcription networks appear to evolve on a faster timescale than the
coding regions of the genes. For example, mice and humans are closely related
and have similar genes.
But their transcription regulation mechanisms and
timescale of protein production are quite different.
1.2 Signs on the Edges
Each edge in a transcription network corresponds to an interaction in which a
transcription factor directly controls the transcription rate of a gene. Such
interactions can be classified into two types.
1. Activation or positive control
2. Repression or negative control
1.2.1 Activation or Positive Control
When a transcription factor binds to the promoter and increases the rate of
transcription it is referred to as activation or positive control. Fig 3 clearly
explains the concept further.
X
Y
Fig 3. Binding of an activator protein (X*)
iIncreases the rate of Transcription of gene Y
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1.2.2 Repression or Negative Control
When a transcription factor binds to the promoter and decreases the rate of
transcription it is referred to as repression or negative control. Fig 4 further
explains in detail.
X
Y
Fig 4. Bound and unbound repressor protein (X*) regulate the rate of transcription of gene Y.
Hence each edge in the network is represented by a plus sign for activation and
a minus sign for repression. Generally transcription networks show more positive
interactions than negative interactions. For example organisms such as E. coli
and yeast show 60-80% activation interactions
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2 References
2.1 Text Book
1. Uri Alon, An Introduction to Systems Biology: Design Principles of
Biological Circuits, 2/e, CRC Press, (2006).
2. Madan Babu M, Bacterial Gene Regulation and Transcriptional Networks,
1/e, Caister Academic Press, (2013).
2.2 Literature References
1. Blais A et al., Constructing Transcptional regulatory networks, Genes &
Dev. ,(2005), 19, 1499-1511.
2. Lee et al., Transcriptional regulatory networks in Saccharomyces
cerevisiae, Science, (2002), 298, 799-804.
3. Potapov et al.,Topology of mammalian transcription networks, Genome.
Inform., (2005), 16, 270-278.
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