Gene Regulation Rev.

Dr. Asmaa Abushady

Gene Regulation
Chapter 14-15

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Quick Revision
◼ The term gene regulation means that the level of
gene expression can vary under different conditions
◼ Genes that are unregulated are termed constitutive
◼ They have essentially constant levels of expression
◼ Frequently, constitutive genes encode proteins that are
continuously necessary for the survival of the organism

◼ The benefit of regulating genes is that encoded

proteins will be produced only when required

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◼ Gene regulation is important for cellular processes
such as
◼ 1. Metabolism
◼ 2. Response to environmental stress
◼ 3. Cell division
◼ The rate of RNA synthesis can be increased or decreased
◼ Transcriptional regulation involves the actions of two main
types of regulatory proteins
◼ Repressors → Bind to DNA and inhibit transcription

◼ Activators → Bind to DNA and increase transcription

◼ Negative control refers to transcriptional regulation by

repressor proteins
◼ Positive control refers to regulation by activator proteins

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◼ Small effector molecules affect transcription regulation
◼ These bind to regulatory proteins but not to DNA directly

◼ In some cases, the presence of a small effector molecule

may increase transcription
◼ These molecules are termed inducers
◼ They function in two ways
◼ Bind activators and cause them to bind to DNA
◼ Bind repressors and prevent them from binding to DNA
◼ Genes that are regulated in this manner are termed inducible

◼ In other cases, the presence of a small effector molecule

may inhibit transcription
◼ Corepressors bind to repressors and cause them to bind to DNA
◼ Inhibitors bind to activators and prevent them from binding to DNA
◼ Genes that are regulated in this manner are termed repressible

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◼ Attenuation can occur in bacteria because transcription and
translation are coupled

◼ During attenuation, transcription actually begins but it is

terminated before the entire mRNA is made
◼ A segment of DNA, termed the attenuator, is important in facilitating
this termination
◼ In the case of the trp operon, transcription terminates shortly past the
trpL region (Figure 14.13c)
◼ Thus attenuation inhibits the further production of tryptophan

◼ The segment of trp operon immediately downstream from

the operator site plays a critical role in attenuation
◼ The first gene in the trp operon is trpL
◼ It encodes a short peptide termed the Leader peptide

◼ Refer to Figure 14.12

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Inducible vs Repressible Regulation
◼ The study of many operons revealed a general trend
concerning inducible versus repressible regulation

◼ Operons involved in catabolism (ie. breakdown of a

substance) are typically inducible
◼ The substance to be broken down (or a related compound) acts
as the inducer

◼ Operons involved in anabolism (ie. biosynthesis of a

substance) are typically repressible
◼ The inhibitor or corepressor is the small molecule that is the
product of the operon

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Translational Regulation
◼ A second way to regulate translation is via the
synthesis of antisense RNA
◼ An RNA strand that is complementary to mRNA

◼ Consider, for example, the trait of osmoregulation

◼ The ability to control the amount of water inside the cell
◼ Must be regulated to prevent shrinkage or lysis

◼ The protein ompF in E. coli is important in osmoregulation

◼ This outer membrane protein is encoded by the ompF gene
◼ OmpF protein is preferentially produced at low osmolarity
◼ At high osmolarity its synthesis is decreased
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Posttranslational Regulation
◼ A common mechanism to regulate the activity of
metabolic enzymes is feedback inhibition

◼ The final product in a pathway often can inhibit the

an enzyme that acts early in the pathway

◼ Refer to Figure 14.15

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◼ Enzyme 1 is an allosteric enzyme,
which means it contains two
different binding sites
◼ Catalytic site → binds substrate
◼ Regulatory site → binds final
product of the pathway

◼ If the concentration of the

final product becomes high
◼ It will bind to enzyme 1
◼ Thereby inhibiting its ability to
convert substrate 1 into
intermediate 1

Figure 14.15
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Posttranslational Regulation
◼ A second strategy to control the function of proteins
is by the covalent modification of their structure
◼ Some modifications are irreversible
◼ Proteolytic processing
◼ Attachment of prosthetic groups, sugars, or lipids
◼ Other modifications are reversible and transiently
affect protein function
◼ Phosphorylation (–PO4)
◼ Acetylation (–COCH3)
◼ Methylation (–CH3)

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INTRODUCTION
◼ Eukaryotic organisms derive many benefits from
regulating their genes
◼ For example
◼ They can respond to changes in nutrient availability
◼ They can respond to environmental stresses

◼ In plants and animals, multicellularity and a more

complex cell structure also demand a much greater
level of gene regulation

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INTRODUCTION
◼ Gene regulation is necessary to ensure
◼ 1. Expression of genes in an accurate pattern during the
various developmental stages of the life cycle
◼ Some genes are only expressed during embryonic stages,
whereas others are only expressed in the adult
◼ 2. Differences among distinct cell types
◼ Nerve and muscle cells look so different because of gene
regulation rather than differences in DNA content

◼ Figure 15.1 describes the steps of gene expression

that are regulated in eukaryotes

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15.1 REGULATORY
TRANSCRIPTION FACTORS
◼ Transcription factors are proteins that influence the
ability of RNA polymerase to transcribe a given gene
◼ There are two main types
◼ General transcription factors
◼ Required for the binding of the RNA pol to the core promoter and
its progression to the elongation stage
◼ Are necessary for basal transcription
◼ Regulatory transcription factors
◼ Serve to regulate the rate of transcription of target genes
◼ They influence the ability of RNA pol to begin transcription of a
particular gene
◼ 2-3% of human genes encode transcription factors

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◼ Regulatory transcription factors recognize cis
regulatory elements located near the core promoter
◼ These sequences are known as control elements,
regulatory elements or regulatory sequences
◼ The binding of regulatory transcription factors to
control elements affects the transcription of an
associated gene
◼ A regulatory protein that increases the rate of
transcription is termed an activator
◼ The sequence it binds is called an enhancer
◼ A regulatory protein that decreases the rate of
transcription is termed a repressor
◼ The sequence it binds is called a silencer

◼ Refer to Figure 15.2

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◼ Most Eukaryotic genes are regulated by many factors
◼ This is known as combinatorial control

◼ Common factors contributing to combinatorial control are:

◼ One or more activator proteins may stimulate transcription
◼ One or more repressor proteins may inhibit transcription
◼ Activators and repressors may be modulated by:
◼ binding of small effector molecules
◼ protein-protein interactions
◼ covalent modifications
◼ Regulatory proteins may alter nucleosomes near the promoter
◼ DNA methylation may inhibit transcription
◼ prevent binding of an activator protein
◼ recruiting proteins that compact the chromatin

◼ Various combinations of these factors can contribute to the

regulation of a single gene
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Enhancers and Silencers
◼ The binding of a transcription factor to an enhancer
increases the rate of transcription
◼ This up-regulation can be 10- to 1,000-fold

◼ The binding of a transcription factor to a silencer

decreases the rate of transcription
◼ This is called down-regulation

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Chromatin Structure
◼ The three-dimensional packing of chromatin is an
important parameter affecting gene expression

◼ Chromatin is a very dynamic structure that can

alternate between two conformations
◼ Closed conformation
◼ Chromatin is very tightly packed
◼ Transcription may be difficult or impossible

◼ Open conformation
◼ Chromatin is accessible to transcription factors
◼ Transcription can take place

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15.3 DNA Methylation
◼ DNA methylation is a change in chromatin structure
that silences gene expression
◼ Carried out by the enzyme DNA methyltransferase
◼ It is common in some eukaryotic species, but not all
◼ Yeast and Drosophila have little DNA methylation
◼ Vertebrates and plants have abundant DNA methylation
◼ In mammals, ~ 2 to 7% of the DNA is methylated

◼ Refer to Figure 15.14

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 Only one strand is
methylated

Both strands are

methylated

Figure 15.14
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◼ DNA methylation usually inhibits the transcription of
eukaryotic genes
◼ Especially when it occurs in the vicinity of the promoter
◼ In vertebrates and plants, many genes contain
CpG islands near their promoters
◼ These CpG islands are 1,000 to 2,000 nucleotides long
◼ Contain high number of CpG sites

◼ In housekeeping genes
◼ The CpG islands are unmethylated
◼ Genes tend to be expressed in most cell types
◼ In tissue-specific genes
◼ The expression of these genes may be silenced by the
methylation of CpG islands
◼ Methylation may influence the binding of transcription factors
◼ Methyl-CpG-binding proteins may recruit factors that lead to
compaction of the chromatin
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 Transcriptional
activator binds to
unmethylated DNA

This would inhibit the

initiation of transcription

Figure 15.15a Transcriptional silencing via methylation

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Figure 15.15b Transcriptional silencing via methylation
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DNA Methylation is Heritable
◼ Methylated DNA sequences are inherited during
cell division
◼ May explain genomic imprinting (Chapter 5)
◼ Specific genes are methylated in gametes from mother or
father
◼ Pattern of one copy of the gene being methylated and the
other not is maintained in the resulting offspring
◼ Figure 15.16 illustrates a model explaining how
methylation is passed from mother to daughter cell

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Figure 15.16

An infrequent and
highly regulated event

DNA methyltransferase
converts hemi-
methylated to fully-
methylated DNA

An efficient and routine

event occurring in
vertebrate and plant cells

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