1) Gene expression in eukaryotes is regulated at multiple levels, including transcription, epigenetic modifications to DNA and histones, alternative splicing of mRNA, and microRNAs inhibiting translation.
2) Transcription is regulated through the binding of transcription factors to enhancer and silencer regions near gene promoters. DNA methylation and histone modifications can alter chromatin structure and gene activity.
3) Alternative splicing of pre-mRNA and the actions of microRNAs introduce additional regulatory mechanisms by generating different protein isoforms from a single gene or inhibiting specific mRNAs post-transcriptionally.
2. 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
3. Chapter 11 Opening Question
How does CREB regulate the expression
of many genes?
4. 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.
6. Concept 11.1 Several Strategies Are Used to Regulate 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 âdecisionâ is
made about which genes to activate.
Two types of regulatory proteinsâalso
called transcription factorsâcontrol
whether a gene is active.
7. Concept 11.1 Several Strategies Are Used to Regulate Gene
Expression
These proteins bind to specific DNA
sequences near the promoter:
⢠Negative regulationâa repressor protein
prevents transcription
⢠Positive regulationâan activator protein
binds to stimulate transcription
10. Concept 11.1 Several Strategies Are Used to Regulate Gene
Expression
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 cycleâin a lysogenic phase,
the viral genome is incorporated into the
host genome and is replicated too.
11. Concept 11.1 Several Strategies Are Used to Regulate Gene
Expression
A bacteriophage may contain DNA or RNA and
may not have a lysogenic phase.
The lytic cycle has two stages:
⢠Early stageâpromoter 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 hostâs chromosome
for synthesis in new viral particles.
12. Concept 11.1 Several Strategies Are Used to Regulate Gene
Expression
⢠Late stageâviral 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.
13. Figure 11.3 A Gene Regulation Strategy for Viral Reproduction
14. Concept 11.1 Several Strategies Are Used to Regulate Gene
Expression
Human immunodeficiency virus (HIV) is a
retrovirus with single-stranded RNA.
HIV is enclosed in a membrane from the
previous host cellâit fuses with the new
host cellâs membrane.
After infection, RNA-directed DNA synthesis
is catalyzed by reverse transcriptase.
Two strands of DNA are synthesized and
reside in the hostâs chromosome as a
provirus.
16. Concept 11.1 Several Strategies Are Used to Regulate Gene
Expression
Host cells have systems to repress the
invading viral genes.
One system uses transcription âterminatorâ
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.
19. 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.
20. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
Uptake and metabolism of lactose involve
three proteins:
âβ-galactoside permeaseâa carrier protein
that moves sugar into the cell
âβ-galactosidaseâan enzyme that
hydrolyses lactose
âβ-galactoside transacetylaseâtransfers
acetyl groups to certain β-galactosides
If E. coli is grown with glucose but no
lactose present, no enzymes for lactose
conversion are produced.
21. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
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.
23. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
Structural genes specify primary protein
structureâthe 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.
24. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
A gene cluster with a single promoter is an
operonâthe 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 operonâturned off unless needed
Repressible operonâturned on unless not
needed
26. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
The lac operon is only transcribed when a
β-galactoside predominates in the cell:
⢠A repressor protein is normally bound to
the operator, which blocks transcription.
⢠In the presence of a β-galactoside, the
repressor detaches and allows RNA
polymerase to initiate transcription.
The key to this regulatory system is the
repressor protein.
29. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
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.
32. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
Difference in two types of operons:
In inducible systemsâa metabolic substrate
(inducer) interacts with a regulatory protein
(repressor); the repressor cannot bind and
allows transcription.
In repressible systemsâa metabolic product
(co-repressor) binds to regulatory protein,
which then binds to the operator and
blocks transcription.
33. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
Generally, inducible systems control
catabolic pathwaysâturned on when
substrate is available
Repressible systems control anabolic
pathwaysâturned on until product
concentration becomes excessive
34. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
Sigma factorsâother 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 sequenceâthey are turned on at
the same time.
Sporulation occurs when nutrients are
depletedâgenes are expressed
sequentially, directed by a sigma factor.
36. 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
sequenceârich in A-T base pairs.
Only after general transcription factors
bind to the core promoter, can RNA
polymerase II bind and initiate
transcription.
37. Figure 11.10 The Initiation of Transcription in Eukaryotes (Part 1)
38. Figure 11.10 The Initiation of Transcription in Eukaryotes (Part 2)
39. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
Besides the promoter, other sequences bind
regulatory proteins that interact with RNA
polymerase and regulate transcription.
Some are positive regulatorsâactivators;
others are negativeârepressors.
DNA sequences that bind activators are
enhancers, those that bind repressors are
silencers.
The combination of factors present
determines the rate of transcription.
41. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
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 genesâ promoters.
The binding produces an induced fitâthe
protein changes conformation.
42. Figure 11.11 A Transcription Factor Protein Binds to DNA
43. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
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 droughtâthe
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.
45. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
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.
46. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
Some cytosine residues in DNA are
modified by adding a methyl group
covalently to the 5Ⲡcarbonâforms 5â˛-
methylcytosine
DNA methyltransferase catalyzes the
reactionâusually in adjacent C and G
residues.
Regions rich in C and G are called CpG
islandsâoften in promoters
49. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
This covalent change in DNA is heritable:
When DNA replicates, a maintenance
methylase catalyzes formation of 5â˛-
methylcytosine in the new strand.
However, methylation pattern may be
alteredâdemethylase can catalyze the
removal of the methyl group.
50. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
Effects of DNA methylation:
⢠Methylated DNA binds proteins that are
involved in repression of transcriptionâ
genes tend to be inactive (silenced).
⢠Patterns of DNA methylation may include
large regions or whole chromosomes.
51. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
Two kinds of chromatin are visible during
interphase:
Euchromatinâdiffuse and light-staining;
contains DNA for mRNA transcription
Heterochromatinâcondensed, dark-
staining; contains genes not transcribed
52. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
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 inactivatedâthis Barr
body is identifiable during interphase and
can be seen in cells of human females.
54. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
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 histoneâs âtail.â
56. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
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.
58. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
Histone deacetylase is another kind of
chromatin remodeling protein.
It can remove the acetyl groups from the
histones, repressing transcription.
59. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription
Factors and DNA Changes
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.
60. 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.
61. Concept 11.4 Eukaryotic Gene Expression Can Be Regulated
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.
63. Concept 11.4 Eukaryotic Gene Expression Can Be Regulated
after Transcription
MicroRNAs(miRNAs)âsmall molecules of
noncoding RNAâare important regulators
of gene expression.
In C. elegans, lin-14 mutations cause the
larvae to skip the first stageâthus the
normal role for lin-14 is to be involved in
stage one of development.
lin-4 mutations cause cells to repeat stage
one eventsâthus the normal role for lin-4
is to negatively regulate lin-14, so that
cells can progress to the next stage of
development.
64. Concept 11.4 Eukaryotic Gene Expression Can Be Regulated
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 describedâonce
transcribed they are guided to a target
mRNA to inhibit its translation and to
degrade the mRNA.
66. Concept 11.4 Eukaryotic Gene Expression Can Be Regulated
after Transcription
mRNA translation can be regulated.
Protein and mRNA concentrations are not
consistently relatedâgoverned by factors
acting after mRNA is made.
Cells either block mRNA translation or alter
how long new proteins persist in the cell.
67. Concept 11.4 Eukaryotic Gene Expression Can Be Regulated
after Transcription
Three ways to regulate mRNA translation:
⢠Inhibition of translation with miRNAs
⢠Modification of the 5Ⲡcap end of mRNA
can be modifiedâif cap is unmodified
mRNA is not translated.
⢠Repressor proteins can block translation
directlyâtranslational repressors
70. 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.