High Throughput Biology

GCMB317
B.Sc. Sem-6
Gene Regulatory Network

Dr Chittabrata Mal
cmal@kol.amity.edu
 GRN

Gene regulatory networks (GRNs) was made possible due to the availability of
high-throughput gene expression data.

Definition 1. We call a network that has been inferred from gene expression data
a “gene regulatory network,” briefly denoted as GRN. (Frank et.al. 2014)

It provide information about regulatory interactions between regulators and their

potential targets; gene-gene interactions, and potential protein-protein
interactions (e.g., in a complex) (de Matos Simoes et al., 2013a).
 Why GRN is Complex?
The results of such GRN depend crucially on the studied conditions, including
• type of the data (simulated, real),
• size of the network,
• number of samples,
• amount of noise,
• experimental design (observational, experimental, interventional),
• type of the underlying interaction structure (scale-free, random, small-world),
• error measure (global, local)

For this reason it is unlikely that there is one “right” method that fits all different
biological, technical and experimental design conditions best.
How Many Gene Regulatory Networks Exist?

Phenotype:
A phenotype results from
molecular and cellular activity
patterns from genotype-
environment interactions.
This implies that each observable
phenotype is associated with
phenotype-specific gene networks,
because without changing
molecular interactions a phenotype
cannot change. In this figure, gene networks can be seen as a bottleneck
between the genotype and the phenotype with respect to their
coupling. That means every change on the genotype level that
will result in a change of the phenotype will also inevitably lead
to a change in the gene network structure as mediator between
both levels.
 Usage of Gene Regulatory Networks

• Causal Map of Molecular Interactions

• Experimental Design and Perturbation Experiments

• Networks as Biomarkers

• Comparative Network Analysis

• Network Medicine and Drug Design

 Tr a n s c r i p t i o n a l G e ne R e gula tory
N e twork

 A set of genes, proteins, small molecules which

interact mutually to control rate of
 In unicellular organisms regulatory networks respond to
transcription
the external environment, to make the cell survival
(Yeast)
 In multicellular organisms regulatory networks control
transcription, cell signaling and development
A gene regulatory network in E. coli_ Nodes are operons. Some operons encode for transcription
factors. transcription factor s regulate other operons
 Structure of a
GRN
 In the network
 Nodes are Genes
 Input is Transcription Factors (proteins)
 Output is Gene Expression
 Arrows show interaction
 GRNs as Control Systems

 The GRNs control organism’s development

 They regulate the expression of thousands of

genes in developmental process
 Regulatory genome acts as a logical processing system
 Causality in the regulatory genome
 Network substructure
 Reengineering genomic control systems
 How GRNs Work?

 GRNs are made up of expression of thousands of

DNA sequences in a cell
 Inputs are signaling pathways and regulatory
proteins known as transcription factors
 Signaling pathways respond to signals and activate the
transcription factor proteins
 Transcription factors bind to genes and make mRNA
 The mRNA synthesizes the required proteins
 Signal 1 Signal 2 Signal 3 Signal 4
... Signal N

Environment

Transcription
factors
X1 X2 X3 ... Xm

Genes

gene 1 gene 2 gene 3 gene 4 gene 5 gene 6... gene k

The mapping between environmental signals, transcription factors

inside the cell and the genes that they regulate
 GRNs and Protein Synthesis

 Specific transcription factors interact with specific

genes to pass on specific genetic information to the
mRNA to synthesize specific proteins for specific
purposes
 Gene expression can be Suppressed or Enhanced
 promot
er
DNA
gene Y

Y protein

TRANSLATION
mRNA
RNA polymerase
TRANSCRIPTION

gene Y

GENE TRANSCRIPTIONAL REGULATION, THE BASIC PICTURE: Each gene is usually preceded by a regulatory DNA
region called the promoter. The promoter contains a specific site (DNA sequence) that can bind RNA polymerase (RNAp), a
complex of several proteins that forms an enzyme That can synthesize mRNA that is complementary to the genes coding
sequence. The process of forming the mRNA is called transcription. The mRNA is then translated into protein.
 X
Activat
X Y
or
gene Y
X binding site
Y
Y
Y
Y
Sx

X X*

X* INCREASED TRANSCRIPTION

Bound activator

An activator X, is a transcription- factor protein that increases the rate of mRNA transcription when it binds the promoter.
The activator transits rapidly between active and inactive forms. In its active form, it has a high affinity to a specific site (or
sites) on the promoter. The signal Sx increases the probability that X is in its active form X*. Thus, X* binds the promoter of
gene Y to increase transcription and production of protein Y. The timescales are typically sub-second for transitions between
X and X*, seconds for binding/ unbinding of X to the promoter, minutes for transcription and translation of the protein
product, and tens of minutes for the accumulation of the protein,
 Bound
Sx
repressor X Y
X X*
NO
TRANSCRIPTION
X*
Bound repressor Y
Y
Unbound repressor Y
Y
X

A repressor X, is a transcription- factor protein that decreases mRNA transcription when it binds the promoter. The signal Sx
increases the probability that X is in its active form X*.X* binds a specific site in the promoter of gene Y to decrease
transcription and production of protein Y. Many genes show a weak (basal) transcription when repressor is bound.
 Negative Feedback System

 Gene encodes a protein inhibiting its own expression

is negative feedback
 Negative feedback is important for homeostasis,
maintenance of system near a desired state
 Positive Feedback System

 Gene encodes a protein activating its own expression

is positive feedback
 Positive feedback is important for differentiation,
evolution
 More Complex Feedback Systems

 Gene encodes a protein activating synthesis of

another protein inhibiting expression of gene: positive
and negative feedback
 Modeling and Analysis of
GRNs

 Extremely complex networks need computational

tools which can answer various questions:
 Behaviors of a system under different conditions?
 Changes in the dynamics of the system if certain parts
stop functioning?
 How robust is the system under extreme conditions?
 Computational Models for
GRNs

 Various computational models have been

developed for regulatory network analysis
 Logical Models; Boolean Networks
 Continuous Networks
 Stochastic Gene Networks
 1) Boolean Networks

 Simplest modeling methodology; logic based

 In a Boolean Network, an entity can attain two levels:

active (1) or inactive (0)
 A gene can be described as expressed or not
expressed at any time
 2) Continuous Networks
• An extension of the Boolean networks

• Genes display a continuous range of activity levels, Continuous

Networks capture several properties of gene regulatory networks
not present in the Boolean model
Grouping of inputs to a node to show level of regulation

• Continuous models allow a comparison of global state

and experimental data and can be more accurate
 3) Stochastic Gene Networks

 Gene expression is a stochastic process; random

time intervals t between occurrence of reactions

 Works on single gene expression and small

synthetic genetic networks

 A function is assigned to each gene, defining the

gene's response to a combination of transcription
factors
 Future Challenges

 Future Challenges include:

 Predicting how genes are regulated in a network?
 Which proteins participate in metabolic pathways and
how they interact?
 How to extract and represent the knowledge of the
genetic regulatory networks?
 Literature
• http://www.brighthub.com/science/genetics/articles/47551.aspx#ixzz192NMwLe6
• The Knowledge Representation of the Genetic Regulatory Networks Based on Ontology, Ines Hamdi, and Mohamed Ben
Ahmed
• Intrinsic noise in gene regulatory networks, Mukund Thattai and Alexander van Oudenaarden*
• Gene regulatory networks and embryonic specification, Leroy Hood* Institute for Systems Biology, 1441 North 34th
Street, Seattle, WA 98103
• From Boolean to Probabilistic Boolean Networks as Models of Genetic Regulatory Networks, ilya shmulevich, member,
ieee, edward r. dougherty, and wei zhang
• Systems Biology: From Physiology to Gene Regulation, By Mustafa Khammash and Hana El-Samad
• https://www.frontiersin.org/articles/10.3389/fcell.2014.00038/full