Regulation of Gene Expression 11. Chapter 11 Regulation of Gene Expression Key Concepts 11.1 Several Strategies Are Used to Regulate Gene Expression 11.2.

Regulation of Gene Expression

11

Chapter 11 Regulation of Gene Expression

Key Concepts

• 11.1 Several Strategies Are Used to Regulate Gene Expression

• 11.2 Many Prokaryotic Genes Are Regulated in Operons

• 11.3 Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes

• 11.4 Eukaryotic Gene Expression Can Be Regulated after Transcription

Chapter 11 Opening Question

How does CREB regulate the expression of many genes?

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


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.


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)


Acellular viruses use gene regulation to take over host cells.

A phage injects a host cell with nucleic acid that takes over synthesis.

New viral particles (virions) appear rapidly and are soon released from the lysed cell.

This lytic cycle is a typical viral reproductive cycle—in a lysogenic phase, the viral genome is incorporated into the host genome and is replicated too.


A bacteriophage may contain DNA or RNA and may not have a lysogenic phase.

The lytic cycle has two stages:

• Early stage—promoter in the viral genome binds host RNA polymerase and adjacent viral genes are transcribed

Early genes shut down transcription of host genes, and stimulate viral replication and transcription of viral late genes.

Host genes are shut down by a posttranscriptional mechanism.

Viral nucleases digest the host’s chromosome for synthesis in new viral particles.


• Late stage—viral late genes are transcribed

They encode the viral capsid proteins and enzymes to lyse the host cell and release new virions.

The whole process from binding and infection to release of new particles takes about 30 minutes.

Figure 11.3 A Gene Regulation Strategy for Viral Reproduction


Human immunodeficiency virus (HIV) is a retrovirus with single-stranded RNA.

HIV is enclosed in a membrane from the previous host cell—it fuses with the new host cell’s membrane.

After infection, RNA-directed DNA synthesis is catalyzed by reverse transcriptase.

Two strands of DNA are synthesized and reside in the host’s chromosome as a provirus.

Figure 11.4 The Reproductive Cycle of HIV


Host cells have systems to repress the invading viral genes.

One system uses transcription “terminator” proteins that interfere with RNA polymerase.

HIV counteracts this negative regulation with Tat (Transactivator of transcription), which allows RNA polymerase to transcribe the viral genome.

Figure 11.5 Regulation of Transcription by HIV (Part 1)

Figure 11.5 Regulation of Transcription by HIV (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.


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


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-4 is to negatively regulate lin-14, so that cells can progress to the next stage of development.


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


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.


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?

Regulation of Gene Expression 11. Chapter 11 Regulation of Gene Expression Key Concepts 11.1 Several Strategies Are Used to Regulate Gene Expression 11.2.

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