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Regulation of Gene

Expression

11

Concept 11.1 Several Strategies Are Used to Regulate Gene

Expression

Gene expression is tightly regulated.

Gene expression may be modified to

counteract environmental changes, or

gene expression may change to alter

function in the cell.

Constitutive proteins are actively

expressed all the time.

Inducible genes are expressed only when

their proteins are needed by the cell.

Figure 11.1 Potential Points for the Regulation of Gene Expression


Expression

Genes can be regulated at the level of

transcription.

Gene expression begins at the promoter

where transcription is initiated.

In selective gene transcription a “decision” is

made about which genes to activate.

Two types of regulatory proteins—also

called transcription factors—control

whether a gene is active.


Expression

These proteins bind to specific DNA

sequences near the promoter:

• Negative regulation—a repressor protein

prevents transcription

• Positive regulation—an activator protein

binds to stimulate transcription

Figure 11.2 Positive and Negative Regulation (Part 1)

Figure 11.2 Positive and Negative Regulation (Part 2)

Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons

Prokaryotes conserve energy by making

proteins only when needed.

In a rapidly changing environment, the most

efficient gene regulation is at the level of

transcription.

E. coli must adapt quickly to food supply

changes. Glucose or lactose may be present.


Uptake and metabolism of lactose involve three proteins:

• -galactoside permease—a carrier protein that moves sugar into the cell

• -galactosidase—an enzyme that hydrolyses lactose

• -galactoside transacetylase—transfers acetyl groups to certain -galactosides

If E. coli is grown with glucose but no lactose present, no enzymes for lactose conversion are produced.


If lactose is predominant and glucose is low, E.

coli synthesizes all three enzymes.

If lactose is removed, synthesis stops.

A compound that induces protein synthesis is

an inducer.

Gene expression and regulating enzyme activity

are two ways to regulate a metabolic pathway.

Figure 11.6 Two Ways to Regulate a Metabolic Pathway


Structural genes specify primary protein

structure—the amino acid sequence.

The three structural genes for lactose enzymes

are adjacent on the chromosome, share a

promoter, and are transcribed together.

Their synthesis is all-or-none.


A gene cluster with a single promoter is an operon—the one that encodes for the lactose enzymes is the lac operon.

An operator is a short stretch of DNA near the promoter that controls transcription of the structural genes.

Inducible operon—turned off unless needed

Repressible operon—turned on unless not needed

Figure 11.7 The lac Operon of E. coli


The lac operon is only transcribed when a

-galactoside predominates in the cell:

• A repressor protein is normally bound to

the operator, which blocks transcription.

• In the presence of a -galactoside, the

repressor detaches and allows RNA

polymerase to initiate transcription.

The key to this regulatory system is the

repressor protein.

Figure 11.8 The lac Operon: An Inducible System (Part 1)

Figure 11.8 The lac Operon: An Inducible System (Part 2)


A repressible operon is switched off when

its repressor is bound to its operator.

However, the repressor only binds in the

presence of a co-repressor.

The co-repressor causes the repressor to

change shape in order to bind to the

promoter and inhibit transcription.

Tryptophan functions as its own co-

repressor, binding to the repressor of the

trp operon.

Figure 11.9 The trp Operon: A Repressible System (Part 1)

Figure 11.9 The trp Operon: A Repressible System (Part 2)


Difference in two types of operons:

In inducible systems—a metabolic substrate

(inducer) interacts with a regulatory protein

(repressor); the repressor cannot bind and

allows transcription.

In repressible systems—a metabolic product

(co-repressor) binds to regulatory protein,

which then binds to the operator and

blocks transcription.


Generally, inducible systems control

catabolic pathways—turned on when

substrate is available

Repressible systems control anabolic

pathways—turned on until product

concentration becomes excessive


Sigma factors—other proteins that bind to

RNA polymerase and direct it to specific

promoters

Global gene regulation: Genes that encode

proteins with related functions may have a

different location but have the same

promoter sequence—they are turned on at

the same time.

Sporulation occurs when nutrients are

depleted—genes are expressed

sequentially, directed by a sigma factor.

Table 11.1 Transcription in Bacteria and Eukaryotes

Concept 11.3 Eukaryotic Genes Are Regulated by Transcription

Factors and DNA Changes

Transcription factors act at eukaryotic promoters.

Each promoter contains a core promoter

sequence where RNA polymerase binds.

TATA box is a common core promoter

sequence—rich in A-T base pairs.

Only after general transcription factors bind to

the core promoter, can RNA polymerase II bind

and initiate transcription.

Figure 11.10 The Initiation of Transcription in Eukaryotes (Part 1)

Figure 11.10 The Initiation of Transcription in Eukaryotes (Part 2)



Besides the promoter, other sequences bind

regulatory proteins that interact with RNA

polymerase and regulate transcription.

Some are positive regulators—activators; others

are negative—repressors.

DNA sequences that bind activators are enhancers,

those that bind repressors are silencers.

The combination of factors present determines the

rate of transcription.

In-Text Art, Ch. 11, p. 216



Transcription factors recognize particular nucleotide

sequences:

NFATs (nuclear factors of activated T cells) are

transcription factors that control genes in the immune

system.

They bind to a recognition sequence near the genes’

promoters.

The binding produces an induced fit—the protein

changes conformation.

Figure 11.11 A Transcription Factor Protein Binds to DNA



Gene expression can be coordinated, even if genes

are far apart on different chromosomes.

They must have regulatory sequences that bind the

same transcription factors.

Plants use this to respond to drought—the

scattered stress response genes each have a

specific regulatory sequence, the dehydration

response element.

During drought, a transcription factor changes

shape and binds to this element.

Figure 11.12 Coordinating Gene Expression



Gene transcription can also be regulated by

reversible alterations to DNA or chromosomal

proteins.

Alterations can be passed on to daughter cells.

These epigenetic changes are different from

mutations, which are irreversible changes to

the DNA sequence.



Some cytosine residues in DNA are modified by adding a methyl group covalently to the 5′ carbon—forms 5′-methylcytosine

DNA methyltransferase catalyzes the reaction—usually in adjacent C and G residues.

Regions rich in C and G are called CpG islands—often in promoters

Figure 11.13 DNA Methylation: An Epigenetic Change (Part 1)

Figure 11.13 DNA Methylation: An Epigenetic Change (Part 2)



This covalent change in DNA is heritable:

When DNA replicates, a maintenance

methylase catalyzes formation of 5′-

methylcytosine in the new strand.

However, methylation pattern may be

altered—demethylase can catalyze the

removal of the methyl group.



Effects of DNA methylation:

• Methylated DNA binds proteins that are involved in repression of transcription—genes tend to be inactive (silenced).

• Patterns of DNA methylation may include

large regions or whole chromosomes.



Two kinds of chromatin are visible during

interphase:

Euchromatin—diffuse and light-staining;

contains DNA for mRNA transcription

Heterochromatin—condensed, dark-

staining; contains genes not transcribed



A type of heterochromatin is the inactive X

chromosome in mammals.

Males (XY) and females (XX) contain

different numbers of X-linked genes, yet

for most genes transcription, rates are

similar.

Early in development, one of the X

chromosomes is inactivated—this Barr

body is identifiable during interphase and

can be seen in cells of human females.

Figure 11.14 X Chromosome Inactivation



Another mechanism for epigenetic

regulation is chromatin remodeling, or

the alteration of chromatin structure.

Nucleosomes contain DNA and positively-

charged histones in a tight complex,

inaccessible to RNA polymerase.

Histone acetyltransferases change the

charge by adding acetyl groups to the

amino acids on the histone’s “tail.”

In-Text Art, Ch. 11, p. 219 (1)



The change in charge opens up the

nucleosomes as histone loses its affinity

for DNA.

More chromatin remodeling proteins bind

and open the DNA for gene expression.

Thus, histone acetyltransferases can

activate transcription.

Figure 11.15 Epigenetic Remodeling of Chromatin for Transcription



Histone deacetylase is another kind of

chromatin remodeling protein.

It can remove the acetyl groups from the

histones, repressing transcription.



Environment plays an important role in

epigenetic modifications.

Even though they are reversible, some

epigenetic changes can permanently alter

gene expression patterns.

If the cells form gametes, the epigenetic

changes can be passed on to the next

generation.

Monozygotic twins show different DNA

methylation patterns after living in different

environments.

Concept 11.4 Eukaryotic Gene Expression Can Be Regulated

after Transcription

Eukaryotic gene expression can be

regulated after the initial gene transcript is

made.

Different mRNAs can be made from the

same gene by alternative splicing.

As introns and exons are spliced out, new

proteins are made.

This may be a deliberate mechanism for

generating proteins with different

functions, from a single gene.


after Transcription

Examples of alternative splicing:

• The HIV genome encodes nine proteins,

but is transcribed as a single pre-mRNA.

• In Drosophila the Sxl gene with four exons

is spliced differently to produce different

combinations in males and females.

Figure 11.16 Alternative Splicing Results in Different Mature mRNAs and Proteins


after Transcription

MicroRNAs(miRNAs)—small molecules of noncoding RNA—are important regulators of gene expression.

In C. elegans, lin-14 mutations cause the larvae to skip the first stage—thus the normal role for lin-14 is to be involved in stage one of development.

lin-4 mutations cause cells to repeat stage one events—thus the normal role for lin-4is to negatively regulate lin-14, so that cells can progress to the next stage of development.


after Transcription

lin-4 encodes not for a protein but for a 22-base miRNA that inhibits lin-14 expression posttranscriptionally by binding to its mRNA.

Many miRNAs have been described—once transcribed they are guided to a target mRNA to inhibit its translation and to degrade the mRNA.

Figure 11.17 mRNA Degradation Caused by MicroRNAs


after Transcription

mRNA translation can be regulated.

Protein and mRNA concentrations are not

consistently related—governed by factors

acting after mRNA is made.

Cells either block mRNA translation or alter

how long new proteins persist in the cell.


after Transcription

Three ways to regulate mRNA translation:

• Inhibition of translation with miRNAs

• Modification of the 5′ cap end of mRNA

can be modified—if cap is unmodified

mRNA is not translated.

• Repressor proteins can block translation

directly—translational repressors

Figure 11.18 A Repressor of Translation

Figure 11.19 A Proteasome Breaks Down Proteins

Answer to Opening Question

The CREB family of transcription factors can

activate or repress gene expression by

binding to the cAMP response element

(CRE) sequence found in the promoter

region of many genes.

CREB binding is essential in many organs,

including the brain, and has been linked to

addiction and memory tasks as well as to

metabolism.

Figure 11.20 An Explanation for Alcoholism?

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