NPTEL – Biotechnology- Systems Biology

Overview of Gene Control

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 NEED FOR GENE REGULATION ................................................................................... 4
1.2 HOW DO EXTERNAL SIGNALS CONTROL GENE EXPRESSION? ........................................ 4
1.3 GENE SWITCHING .................................................................................................... 5
1.4 GENE CONTROL IN EUKARYOTIC SYSTEMS ................................................................ 6
2 REFERENCES ........................................................................................................... 10
2.1 TEXT BOOKS........................................................................................................... 10
2.2 LITERATURE REFERENCES ...................................................................................... 10

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1 Introduction
A major functional theme of interest to cell biologists is gene expression. What does the
term ‘gene expression’ actually mean? It refers to the process of genes being switched
ON to produce a product. The product could be an enzyme, a structural protein or
molecular player that controls the expression. Generally gene expression studies focus
on the measurement of mRNA production predominantly because the expression of a
gene is controlled at the level of transcription when mRNA is synthesized. However, one
can also relate to downstream events which control the rate of protein synthesis and
hence control gene expression. The expression pattern of a cell is embedded in the
spatio temporal expression of its genes. An intriguing question in the field of cell biology
and genomics is how cells of a multi cellular organism accommodating the same
genome show differential gene expression. The process of cellular differentiation (when
the cell lineage is decided) is effectively controlled by the patterns of the gene
expression in the cell. A typical human cell expresses only a fraction of genes at any
point of time. Studies on a variety of mRNAs have established that a typical human cell
expresses around 10,000 of its approximately 25,000 genes. Comparisons of mRNA
expression patterns in a series of human cell lines show varied expression across cell
types.
How does the cell decide on which of its several thousand genes should be expressed
at a particular time? Where is the inherent control mechanism embedded in the cell?
And how is this effected in a spatio temporal manner? And yet another question of
interest in cell biology is to understand why should there be a control on gene
expression.

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1.1 Need for Gene Regulation

The biochemical processes and signalling inside cells is mostly enzyme driven and are
energy dependent. The enzymatic proteins which affect these processes are products
of gene transcription and translation. These genes are switched on or off depend on the
requirements of the time scales.
Gene switching happens due to a variety of reasons, some of which are listed below:
1. Selective switching of genes prevents wastage of energy and cellular resources.
Many genes posses the natural capability to switch ON or switch OFF genes
based on their requirements
2. Gene switching events are one of the key processes required at development
phases of multi cellular organisms during cell fate decisions
3. Unregulated gene expression leads to diseases for example, the onset of cancer
can be attributed to aberrant gene expression pattern where cancer cells lose
their ability to regulate mitosis-an uncontrolled cell division.

1.2 How do external signals control gene expression?

Extra cellular cues from the environment like temperature, changes in pH and changes
in internal biochemical signalling have been shown to alter gene expression to a
significant extent. The response of a liver cell to the steroid- gluoco corticoid hormone is
a striking example of altered gene expression. Gluoco corticoid hormones are released
in the body during starvation or during extreme activity of exercising. Gluoco corticoid
signalling in liver enhances glucose production and alters expression of tyrosine amino
transferase which aids the conversion from tyrosine to glucose. In the absence of the
hormone, basal levels of these enzymes are maintained at basic levels. Adipose cells
respond differently to gluoco corticoids. When a fat cell is exposed to gluoco corticoid,
the levels of tyrosine amino transferases are reduced. Some of the cell types do not
respond to gluoco corticoid at all. We therefore understand that the same extracellular
signal elicits different responses from different cell types.

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1.3 Gene Switching

A differentiated cell example neuronal cell performs its unique and specific function by
switching ON a specific set of genes and by switching OFF another. Some of these
genes are permanently active (switched ON) because they carry out vital functions of
the cell and because they contain the blueprint for vital enzymes required for cellular
function. Certain genes not required for a particular function in the cell may be switched
OFF. The production of insulin in pancreatic cell signals the ON state of the insulin gene
while other genes irrelevant for insulin signalling may be switched OFF.
The level of expression of a specific gene in a cell is a major factor in the expression
control mechanism. For example, the amount of melanin expressed by the skin cell
decides the color of the skin. Melanin production is under the type control of two genes
each of which show dominant and recessive expression as represented in Fig 1.

Fig 1. Genotypes and phenotypes expressed by 2 melanin genes (dominant and recessive)

The Fig illustrates 5 possible genotypes that the melanin gene can express. We find
that 4 dominant alleles represent enhanced expression of melanin leading to the
phenotype of black skin.

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1.4 Gene Control in Eukaryotic Systems

Studying gene control in eukaryotic cells is an active and attractive pursuit for
experimental biologists. The term ‘Eukaryotic Gene Control’ is not restricted to the
process of transcribing to mRNA. For example, the transcription units for mRNAs do not
mark the final mRNA product in the case of vertebrate cells. Several control points
exists from the processing of primary RNA transcripts in the cell nucleus till the mRNA is
translated in the cytoplasm. Specifically the eukaryotic genes undergo more levels of
regulation than the bacterial genes. Transcription regulation, RNA processing in the
nucleus, mRNA stability, and the frequency of translation events in the cytoplasm are
the vital steps at which eukaryotic genes exercise control in expression. The same has
been illustrated in Fig 2.

Fig 2. Gene regulatory pathways extending from the nucleus to the cytoplasm of a typical eukaryotic cell

The transcription process in eukaryotic cells is more complex than in the prokaryotic
systems. Gene regulation in these systems can be effected in two ways as shown in the
Fig 3.

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Fig 3. Mechanisms of gene regulation in eukaryotes

The regulation could be effected through

1. Control mechanisms that involve change in DNA content or position. Here the DNA
of somatic cells can be altered but these changes do not affect gametes so that
they are not inherited by the offspring.
2. Control mechanisms involving changes in expression patterns. Regulatory
mechanisms involving change in DNA content or position involves alterations at the
level of the gene and may be due to
(a) Gene loss
(b) Gene amplification
(c) Gene rearrangement
Regulatory mechanisms involving changes in expression pattern include
(a) Transcriptional control
(b) Post-transcriptional control
(c) Translational control
(d) Post-translational control

Gene alteration is one of the key mechanisms of gene regulation in eukaryotes. This
may be carried out through mechanisms like gene loss, gene amplification or through
gene rearrangement. Gene alteration plays a role in regulating gene expression under
developmental stages, drug resistance etc. Gene loss involves elimination of the gene
from differentiating cells in protozoans as well as in metazoans. Lineage specific gene

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loss is a major evolutionary process studied from gene sets of completely sequenced
genomes. In prokaryotes, gene loss and horizontal gene transfer contributes to an
intensive gene flux that shapes the genomes of these organisms. In eukaryotes lineage
specific gene loss is greater than in prokaryotes. A very strong selection pressures
result in dramatic gene loss. For example, Encephalitozoon cuniculi is a eukaryotic
intracellular parasite, which now has been estimated to have approximately 2000 genes
compared to around 6000 genes in the genomes of yeast, representing a striking case
of massive gene loss. Complete chromosomes are preserved only in cells serving as
precursors for gamete formation.

Gene amplification refers to a selective increase in the number of copies of a gene

sequence. Cancer cells produce multiple copies of genes due to extra cellular signalling
or in response to signals from the environment. Hence gene amplification occurs during
malignancy and in certain cases cells become resistant to drugs due to the process of
gene amplification. Cancer cells when treated with methotrexate which blocks
dihydrofolate reductase undergo gene amplification producing dihydrofolate reductase
in abundant amount to circumvent the effect of methotrexate. The term ’gene
amplification’ is often used to refer to the laboratory technique called ‘polymerase Chain
Reaction’ which enables amplifying gene sequences in an eppendorf tube.

Gene rearrangement involves the translocation of a gene from one region of a genome
to another. This involves rearrangement of substantial stretches of DNA in the somatic
cells and can alter gene expression. Transposons are DNA stretches that move across
locations within the genome. These transposons control gene expression depending on
their location. For example, if the transposon is inserted in a transcription regulatory
sequence it regulates the levels of protein production. It may also carry a gene that is
activated if it is inserted downstream of a promoter sequence. Mammalian systems
such as mouse or human being synthesize large amounts of specific antibodies against
any foreign antigens on exposure. Antibodies are composed of two heavy and two light
chains. The specificity of the antibody is determined by the amino acid sequences of the
variable regions of both the light and the heavy chains. The rearrangement of various
immunoglobulin genes leads to the formation of a variety of antibodies specific for

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diverse antigens. African Trypanosomes sequentially express various surface antigens

in their mammalian host. The expression of such Variable Surface Glycoprotein (VSG)
antigens has been shown to be related to DNA rearrangements. (Williams R. et al.,
Nature 1979, Payes et al. PNAS 1981). Trypanosomes circumvent host defense by
replacing a copy of VSG (Variant Surface Glycoprotein) gene at the expression site by
another VSG gene at some other site.

We shall discuss in the next class how changes in gene expression can be brought
about at the level of transcription, translation and at the level of post transcription and
post translation through precise regulatory mechanisms that control expressions.

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2 References

2.1 Text Books

1. David S. Latchman, Gene Control,1/e, Garland Science Publications, (2010).

2. Alberts B. Johnson A, Lewis J , Molecular Biology of the cell, 4/e, (2002).

2.2 Literature References

1. D A Day and M F Tuite, Post-transcriptional gene regulatory mechanisms in

eukaryotes: an overview, Journal of Endocrinology (1998), 157, 361-371.
2. Bonnie Burgess-Beusse, Catherine et al., The insulation of genes from external
enhancers and silencing chromatin, PNAS, (2002), 99, 16433–16437.

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