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Chapter 18

Regulation of Gene Expression

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Overview: Conducting the Genetic Orchestra

Prokaryotes and eukaryotes alter gene expression in response to their changing environment
In multicellular eukaryotes, gene expression regulates development and is responsible for differences in cell types
RNA molecules play many roles in regulating gene expression in eukaryotes

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Fig. 18-1

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Concept 18.1: Bacteria often respond to environmental change by regulating transcription

Natural selection has favored bacteria that produce only the products needed by that cell
A cell can regulate the production of enzymes by feedback inhibition or by gene regulation
Gene expression in bacteria is controlled by the operon model

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Fig. 18-2

Regulation

of gene

expression

trpE gene

trpD gene

trpC gene

trpB gene

trpA gene

(b) Regulation of enzyme

production

(a) Regulation of enzyme

activity

Enzyme 1

Enzyme 2

Enzyme 3

Tryptophan

Precursor

Feedback

inhibition

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Operons: The Basic Concept

A cluster of functionally related genes can be under coordinated control by a single on-off “switch”
The regulatory “switch” is a segment of DNA called an operator usually positioned within the promoter
An operon is the entire stretch of DNA that includes the operator, the promoter, and the genes that they control

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The operon can be switched off by a protein repressor
The repressor prevents gene transcription by binding to the operator and blocking RNA polymerase
The repressor is the product of a separate regulatory gene

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The repressor can be in an active or inactive form, depending on the presence of other molecules
A corepressor is a molecule that cooperates with a repressor protein to switch an operon off
For example, E. coli can synthesize the amino acid tryptophan

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By default the trp operon is on and the genes for tryptophan synthesis are transcribed
When tryptophan is present, it binds to the trp repressor protein, which turns the operon off
The repressor is active only in the presence of its corepressor tryptophan; thus the trp operon is turned off (repressed) if tryptophan levels are high

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Fig. 18-3

Polypeptide subunits that make up

enzymes for tryptophan synthesis

(b) Tryptophan present, repressor active, operon off

Tryptophan

(corepressor)

(a) Tryptophan absent, repressor inactive, operon on

No RNA made

Active

repressor

mRNA

Protein

DNA

mRNA 5′

Protein

Inactive

repressor

RNA

polymerase

Regulatory

gene

Promoter

trp operon

Genes of operon

Operator

Stop codon

Start codon

mRNA

trpA

5′

3′

trpR

trpE

trpD

trpC

trpB

A

B

C

D

E

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Fig. 18-3a

Polypeptide subunits that make up

enzymes for tryptophan synthesis

(a) Tryptophan absent, repressor inactive, operon on

DNA

mRNA 5′

Protein

Inactive

repressor

RNA

polymerase

Regulatory

gene

Promoter

trp operon

Genes of operon

Operator

Stop codon

Start codon

mRNA

trpA

5′

3′

trpR

trpE

trpD

trpC

trpB

A

B

C

D

E

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Fig. 18-3b-1

(b) Tryptophan present, repressor active, operon off

Tryptophan

(corepressor)

No RNA made

Active

repressor

mRNA

Protein

DNA

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Fig. 18-3b-2

(b) Tryptophan present, repressor active, operon off

Tryptophan

(corepressor)

No RNA made

Active

repressor

mRNA

Protein

DNA

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Repressible and Inducible Operons: Two Types of Negative Gene Regulation

A repressible operon is one that is usually on; binding of a repressor to the operator shuts off transcription
The trp operon is a repressible operon
An inducible operon is one that is usually off; a molecule called an inducer inactivates the repressor and turns on transcription

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The lac operon is an inducible operon and contains genes that code for enzymes used in the hydrolysis and metabolism of lactose
By itself, the lac repressor is active and switches the lac operon off
A molecule called an inducer inactivates the repressor to turn the lac operon on

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Fig. 18-4

(b) Lactose present, repressor inactive, operon on

(a) Lactose absent, repressor active, operon off

mRNA

Protein

DNA

mRNA 5′

Protein

Active

repressor

RNA

polymerase

Regulatory

gene

Promoter

Operator

mRNA

5′

3′

Inactive

repressor

Allolactose

(inducer)

5′

3′

No

RNA

made

RNA

polymerase

Permease

Transacetylase

lac operon

β-Galactosidase

lacY

lacZ

lacA

lacI

lacZ

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Fig. 18-4a

(a) Lactose absent, repressor active, operon off

DNA

Protein

Active

repressor

RNA

polymerase

Regulatory

gene

Promoter

Operator

mRNA

5′

3′

No

RNA

made

lacI

lacZ

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Fig. 18-4b

(b) Lactose present, repressor inactive, operon on

mRNA

Protein

DNA

mRNA 5′

Inactive

repressor

Allolactose

(inducer)

5′

3′

RNA

polymerase

Permease

Transacetylase

lac operon

β-Galactosidase

lacY

lacZ

lacA

lacI

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Inducible enzymes usually function in catabolic pathways; their synthesis is induced by a chemical signal
Repressible enzymes usually function in anabolic pathways; their synthesis is repressed by high levels of the end product
Regulation of the trp and lac operons involves negative control of genes because operons are switched off by the active form of the repressor

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Positive Gene Regulation

Some operons are also subject to positive control through a stimulatory protein, such as catabolite activator protein (CAP), an activator of transcription
When glucose (a preferred food source of E. coli) is scarce, CAP is activated by binding with cyclic AMP
Activated CAP attaches to the promoter of the lac operon and increases the affinity of RNA polymerase, thus accelerating transcription

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When glucose levels increase, CAP detaches from the lac operon, and transcription returns to a normal rate
CAP helps regulate other operons that encode enzymes used in catabolic pathways

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Fig. 18-5

(b) Lactose present, glucose present (cAMP level

low): little lac mRNA synthesized

cAMP

DNA

Inactive lac

repressor

Allolactose

Inactive

CAP

lacI

CAP-binding site

Promoter

Active

CAP

Operator

lacZ

RNA

polymerase

binds and

transcribes

Inactive lac

repressor

lacZ

Operator

Promoter

DNA

CAP-binding site

lacI

RNA

polymerase less

likely to bind

Inactive

CAP

(a) Lactose present, glucose scarce (cAMP level

high): abundant lac mRNA synthesized

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Concept 18.2: Eukaryotic gene expression can be regulated at any stage

All organisms must regulate which genes are expressed at any given time
In multicellular organisms gene expression is essential for cell specialization

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Differential Gene Expression

Almost all the cells in an organism are genetically identical
Differences between cell types result from differential gene expression, the expression of different genes by cells with the same genome
Errors in gene expression can lead to diseases including cancer
Gene expression is regulated at many stages

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Fig. 18-6

DNA

Signal

Gene

NUCLEUS

Chromatin modification

Chromatin

Gene available

for transcription

Exon

Intron

Tail

RNA

Cap

RNA processing

Primary transcript

mRNA in nucleus

Transport to cytoplasm

mRNA in cytoplasm

Translation

CYTOPLASM

Degradation

of mRNA

Protein processing

Polypeptide

Active protein

Cellular function

Transport to cellular

destination

Degradation

of protein

Transcription

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Fig. 18-6a

DNA

Signal

Gene

NUCLEUS

Chromatin modification

Chromatin

Gene available

for transcription

Exon

Intron

Tail

RNA

Cap

RNA processing

Primary transcript

mRNA in nucleus

Transport to cytoplasm

CYTOPLASM

Transcription

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Fig. 18-6b

mRNA in cytoplasm

Translation

CYTOPLASM

Degradation

of mRNA

Protein processing

Polypeptide

Active protein

Cellular function

Transport to cellular

destination

Degradation

of protein

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Regulation of Chromatin Structure

Genes within highly packed heterochromatin are usually not expressed
Chemical modifications to histones and DNA of chromatin influence both chromatin structure and gene expression

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Histone Modifications

In histone acetylation, acetyl groups are attached to positively charged lysines in histone tails
This process loosens chromatin structure, thereby promoting the initiation of transcription
The addition of methyl groups (methylation) can condense chromatin; the addition of phosphate groups (phosphorylation) next to a methylated amino acid can loosen chromatin

Animation: DNA Packing

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Fig. 18-7

Histone

tails

DNA

double helix

(a) Histone tails protrude outward from a

nucleosome

Acetylated histones

Amino

acids

available

for chemical

modification

(b) Acetylation of histone tails promotes loose

chromatin structure that permits transcription

Unacetylated histones

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The histone code hypothesis proposes that specific combinations of modifications help determine chromatin configuration and influence transcription

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DNA Methylation

DNA methylation, the addition of methyl groups to certain bases in DNA, is associated with reduced transcription in some species
DNA methylation can cause long-term inactivation of genes in cellular differentiation
In genomic imprinting, methylation regulates expression of either the maternal or paternal alleles of certain genes at the start of development

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Epigenetic Inheritance

Although the chromatin modifications just discussed do not alter DNA sequence, they may be passed to future generations of cells
The inheritance of traits transmitted by mechanisms not directly involving the nucleotide sequence is called epigenetic inheritance

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Regulation of Transcription Initiation

Chromatin-modifying enzymes provide initial control of gene expression by making a region of DNA either more or less able to bind the transcription machinery

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Organization of a Typical Eukaryotic Gene

Associated with most eukaryotic genes are control elements, segments of noncoding DNA that help regulate transcription by binding certain proteins
Control elements and the proteins they bind are critical to the precise regulation of gene expression in different cell types

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Fig. 18-8-1

Enhancer

(distal control elements)

Proximal

control elements

Poly-A signal

sequence

Termination

region

Downstream

Promoter

Upstream

DNA

Exon

Intron

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Fig. 18-8-2

Enhancer

(distal control elements)

Proximal

control elements

Poly-A signal

sequence

Termination

region

Downstream

Promoter

Upstream

DNA

Exon

Intron

Cleaved 3′ end

of primary

transcript

Primary RNA

transcript

Poly-A

signal

Transcription

5′

Exon

Intron

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Fig. 18-8-3

Enhancer

(distal control elements)

Proximal

control elements

Poly-A signal

sequence

Termination

region

Downstream

Promoter

Upstream

DNA

Exon

Intron

Exon

Intron

Cleaved 3′ end

of primary

transcript

Primary RNA

transcript

Poly-A

signal

Transcription

5′

RNA processing

Intron RNA

Coding segment

mRNA

5′ Cap

5′ UTR

Start

codon

Stop

codon

3′ UTR

Poly-A

tail

3′

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The Roles of Transcription Factors

To initiate transcription, eukaryotic RNA polymerase requires the assistance of proteins called transcription factors
General transcription factors are essential for the transcription of all protein-coding genes
In eukaryotes, high levels of transcription of particular genes depend on control elements interacting with specific transcription factors

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Proximal control elements are located close to the promoter
Distal control elements, groups of which are called enhancers, may be far away from a gene or even located in an intron

Enhancers and Specific Transcription Factors

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An activator is a protein that binds to an enhancer and stimulates transcription of a gene
Bound activators cause mediator proteins to interact with proteins at the promoter

Animation: Initiation of Transcription

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Fig. 18-9-1

Enhancer

TATA

box

Promoter

Activators

DNA

Gene

Distal control

element

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Fig. 18-9-2

Enhancer

TATA

box

Promoter

Activators

DNA

Gene

Distal control

element

Group of

mediator proteins

DNA-bending

protein

General

transcription

factors

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Fig. 18-9-3

Enhancer

TATA

box

Promoter

Activators

DNA

Gene

Distal control

element

Group of

mediator proteins

DNA-bending

protein

General

transcription

factors

RNA

polymerase II

RNA

polymerase II

Transcription

initiation complex

RNA synthesis

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Some transcription factors function as repressors, inhibiting expression of a particular gene
Some activators and repressors act indirectly by influencing chromatin structure to promote or silence transcription

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A particular combination of control elements can activate transcription only when the appropriate activator proteins are present

Combinatorial Control of Gene Activation

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Fig. 18-10

Control

elements

Enhancer

Available

activators

Albumin gene

(b) Lens cell

Crystallin gene

expressed

Available

activators

LENS CELL

NUCLEUS

LIVER CELL

NUCLEUS

Crystallin gene

Promoter

(a) Liver cell

Crystallin gene

not expressed

Albumin gene

expressed

Albumin gene

not expressed

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Coordinately Controlled Genes in Eukaryotes

Unlike the genes of a prokaryotic operon, each of the coordinately controlled eukaryotic genes has a promoter and control elements
These genes can be scattered over different chromosomes, but each has the same combination of control elements
Copies of the activators recognize specific control elements and promote simultaneous transcription of the genes

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Mechanisms of Post-Transcriptional Regulation

Transcription alone does not account for gene expression
Regulatory mechanisms can operate at various stages after transcription
Such mechanisms allow a cell to fine-tune gene expression rapidly in response to environmental changes

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RNA Processing

In alternative RNA splicing, different mRNA molecules are produced from the same primary transcript, depending on which RNA segments are treated as exons and which as introns

Animation: RNA Processing

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Fig. 18-11

or

RNA splicing

mRNA

Primary

RNA

transcript

Troponin T gene

Exons

DNA

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mRNA Degradation

The life span of mRNA molecules in the cytoplasm is a key to determining protein synthesis
Eukaryotic mRNA is more long lived than prokaryotic mRNA
The mRNA life span is determined in part by sequences in the leader and trailer regions

Animation: mRNA Degradation

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Initiation of Translation

The initiation of translation of selected �mRNAs can be blocked by regulatory proteins that bind to sequences or structures of the mRNA
Alternatively, translation of all mRNAs �in a cell may be regulated simultaneously
For example, translation initiation factors are simultaneously activated in an egg following fertilization

Animation: Blocking Translation

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Protein Processing and Degradation

After translation, various types of protein processing, including cleavage and the addition of chemical groups, are subject to control
Proteasomes are giant protein complexes that bind protein molecules and degrade them

Animation: Protein Degradation

Animation: Protein Processing

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Fig. 18-12

Proteasome

and ubiquitin

to be recycled

Proteasome

Protein

fragments

(peptides)

Protein entering a

proteasome

Ubiquitinated

protein

Protein to

be degraded

Ubiquitin

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Concept 18.3: Noncoding RNAs play multiple roles in controlling gene expression

Only a small fraction of DNA codes for proteins, rRNA, and tRNA
A significant amount of the genome may be transcribed into noncoding RNAs
Noncoding RNAs regulate gene expression at two points: mRNA translation and chromatin configuration

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Effects on mRNAs by MicroRNAs and Small Interfering RNAs

MicroRNAs (miRNAs) are small single-stranded RNA molecules that can bind to mRNA
These can degrade mRNA or block its translation

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Fig. 18-13

miRNA-

protein

complex

(a) Primary miRNA transcript

Translation blocked

Hydrogen

bond

(b) Generation and function of miRNAs

Hairpin

miRNA

Dicer

3′

mRNA degraded

5′

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The phenomenon of inhibition of gene expression by RNA molecules is called RNA interference (RNAi)
RNAi is caused by small interfering RNAs (siRNAs)
siRNAs and miRNAs are similar but form from different RNA precursors

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Chromatin Remodeling and Silencing of Transcription by Small RNAs

siRNAs play a role in heterochromatin formation and can block large regions of the chromosome
Small RNAs may also block transcription of specific genes

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Concept 18.4: A program of differential gene expression leads to the different cell types in a multicellular organism

During embryonic development, a fertilized egg gives rise to many different cell types
Cell types are organized successively into tissues, organs, organ systems, and the whole organism
Gene expression orchestrates the developmental programs of animals

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A Genetic Program for Embryonic Development

The transformation from zygote to adult results from cell division, cell differentiation, and morphogenesis

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Fig. 18-14

(a) Fertilized eggs of a frog

(b) Newly hatched tadpole

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Fig. 18-14a

(a) Fertilized eggs of a frog

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Fig. 18-14b

(b) Newly hatched tadpole

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Cell differentiation is the process by which cells become specialized in structure and function
The physical processes that give an organism its shape constitute morphogenesis
Differential gene expression results from genes being regulated differently in each cell type
Materials in the egg can set up gene regulation that is carried out as cells divide

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Cytoplasmic Determinants and Inductive Signals

An egg’s cytoplasm contains RNA, proteins, and other substances that are distributed unevenly in the unfertilized egg
Cytoplasmic determinants are maternal substances in the egg that influence early development
As the zygote divides by mitosis, cells contain different cytoplasmic determinants, which lead to different gene expression

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Fig. 18-15

(b) Induction by nearby cells

(a) Cytoplasmic determinants in the egg

Two different

cytoplasmic

determinants

Unfertilized egg cell

Sperm

Fertilization

Zygote

Mitotic

cell division

Two-celled

embryo

Signal

molecule

(inducer)

Signal

transduction

pathway

Early embryo

(32 cells)

Nucleus

NUCLEUS

Signal

receptor

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Fig. 18-15a

(a) Cytoplasmic determinants in the egg

Two different

cytoplasmic

determinants

Unfertilized egg cell

Sperm

Fertilization

Zygote

Mitotic

cell division

Two-celled

embryo

Nucleus

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Fig. 18-15b

(b) Induction by nearby cells

Signal

molecule

(inducer)

Signal

transduction

pathway

Early embryo

(32 cells)

NUCLEUS

Signal

receptor

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The other important source of developmental information is the environment around the cell, especially signals from nearby embryonic cells
In the process called induction, signal molecules from embryonic cells cause transcriptional changes in nearby target cells
Thus, interactions between cells induce differentiation of specialized cell types

Animation: Cell Signaling

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Sequential Regulation of Gene Expression During Cellular Differentiation

Determination commits a cell to its final fate
Determination precedes differentiation
Cell differentiation is marked by the production of tissue-specific proteins

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Myoblasts produce muscle-specific proteins and form skeletal muscle cells
MyoD is one of several “master regulatory genes” that produce proteins that commit the cell to becoming skeletal muscle
The MyoD protein is a transcription factor that binds to enhancers of various target genes

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Fig. 18-16-1

Embryonic

precursor cell

Nucleus

OFF

DNA

Master regulatory gene myoD

Other muscle-specific genes

OFF

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Fig. 18-16-2

Embryonic

precursor cell

Nucleus

OFF

DNA

Master regulatory gene myoD

Other muscle-specific genes

OFF

mRNA

MyoD protein

(transcription

factor)

Myoblast

(determined)

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Fig. 18-16-3

Embryonic

precursor cell

Nucleus

OFF

DNA

Master regulatory gene myoD

Other muscle-specific genes

OFF

mRNA

MyoD protein

(transcription

factor)

Myoblast

(determined)

mRNA

Myosin, other

muscle proteins,

and cell cycle–

blocking proteins

Part of a muscle fiber

(fully differentiated cell)

MyoD

Another

transcription

factor

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Pattern Formation: Setting Up the Body Plan

Pattern formation is the development of a spatial organization of tissues and organs
In animals, pattern formation begins with the establishment of the major axes
Positional information, the molecular cues that control pattern formation, tells a cell its location relative to the body axes and to neighboring cells

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Pattern formation has been extensively studied in the fruit fly Drosophila melanogaster
Combining anatomical, genetic, and biochemical approaches, researchers have discovered developmental principles common to many other species, including humans

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The Life Cycle of Drosophila

In Drosophila, cytoplasmic determinants in the unfertilized egg determine the axes before fertilization
After fertilization, the embryo develops into a segmented larva with three larval stages

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Fig. 18-17

Thorax

Head

Abdomen

0.5 mm

Dorsal

Ventral

Right

Posterior

Left

AXES

Follicle cell

(a) Adult

Nucleus

Egg

cell

Nurse cell

Egg cell

developing within

ovarian follicle

Unfertilized egg

Fertilized egg

Depleted

nurse cells

Egg

shell

Fertilization

Laying of egg

Body

segments

Embryonic

development

Hatching

0.1 mm

Segmented

embryo

Larval stage

(b) Development from egg to larva

1

2

3

4

5

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Fig. 18-17a

Thorax

Head

Abdomen

0.5 mm

Dorsal

Ventral

Right

Posterior

Left

AXES

(a) Adult

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Fig. 18-17b

Follicle cell

Nucleus

Egg

cell

Nurse cell

Egg cell

developing within

ovarian follicle

Unfertilized egg

Fertilized egg

Depleted

nurse cells

Egg

shell

Fertilization

Laying of egg

Body

segments

Embryonic

development

Hatching

0.1 mm

Segmented

embryo

Larval stage

(b) Development from egg to larva

1

2

3

4

5

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Genetic Analysis of Early Development: Scientific Inquiry

Edward B. Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus won a Nobel 1995 Prize for decoding pattern formation in Drosophila
Lewis demonstrated that genes direct the developmental process

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Fig. 18-18

Antenna

Mutant

Wild type

Eye

Leg

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Fig. 18-18a

Antenna

Wild type

Eye

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Fig. 18-18b

Mutant

Leg

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Nüsslein-Volhard and Wieschaus studied segment formation
They created mutants, conducted breeding experiments, and looked for corresponding genes
Breeding experiments were complicated by embryonic lethals, embryos with lethal mutations
They found 120 genes essential for normal segmentation

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Axis Establishment

Maternal effect genes encode for cytoplasmic determinants that initially establish the axes of the body of Drosophila
These maternal effect genes are also called egg-polarity genes because they control orientation of the egg and consequently the fly

Animation: Development of Head-Tail Axis in Fruit Flies

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One maternal effect gene, the bicoid gene, affects the front half of the body
An embryo whose mother has a mutant bicoid gene lacks the front half of its body and has duplicate posterior structures at both ends

Bicoid: A Morphogen Determining Head

Structures

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Fig. 18-19

Tail

Head

Wild-type larva

T1

T2

T3

A1

A2

A3

A4

A5

A6

A7

A8

A7

A6

A7

A8

Mutant larva (bicoid)

EXPERIMENT

RESULTS

CONCLUSION

Fertilization,

translation

of bicoid

mRNA

Bicoid protein in early

embryo

Anterior end

Bicoid mRNA in mature

unfertilized egg

100 µm

bicoid mRNA

Nurse cells

Egg

Developing egg

Bicoid mRNA in mature unfertilized egg

Bicoid protein in early embryo

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Fig. 18-19a

T1

T2

T3

A1

A2

A3

A4

A5

A6

A7

A8

A7

A6

A7

Tail

Head

Wild-type larva

Mutant larva (bicoid)

EXPERIMENT

A8

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Fig. 18-19b

Fertilization,

translation

of bicoid

mRNA

Bicoid protein in early

embryo

Anterior end

Bicoid mRNA in mature

unfertilized egg

100 µm

RESULTS

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Fig. 18-19c

bicoid mRNA

Nurse cells

Egg

Developing egg

Bicoid mRNA in mature

unfertilized egg

Bicoid protein

in early embryo

CONCLUSION

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This phenotype suggests that the product of the mother’s bicoid gene is concentrated at the future anterior end
This hypothesis is an example of the gradient hypothesis, in which gradients of substances called morphogens establish an embryo’s axes and other features

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The bicoid research is important for three reasons:

– It identified a specific protein required for some early steps in pattern formation

– It increased understanding of the mother’s role in embryo development

– It demonstrated a key developmental principle that a gradient of molecules can determine polarity and position in the embryo

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Concept 18.5: Cancer results from genetic changes that affect cell cycle control

The gene regulation systems that go wrong during cancer are the very same systems involved in embryonic development

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Types of Genes Associated with Cancer

Cancer can be caused by mutations to genes that regulate cell growth and division
Tumor viruses can cause cancer in animals including humans

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Oncogenes and Proto-Oncogenes

Oncogenes are cancer-causing genes
Proto-oncogenes are the corresponding normal cellular genes that are responsible for normal cell growth and division
Conversion of a proto-oncogene to an oncogene can lead to abnormal stimulation of the cell cycle

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Fig. 18-20

Normal growth-

stimulating

protein in excess

New

promoter

DNA

Proto-oncogene

Gene amplification:

Translocation or

transposition:

Normal growth-stimulating

protein in excess

Normal growth-

stimulating

protein in excess

Hyperactive or

degradation-

resistant protein

Point mutation:

Oncogene

within a control element

within the gene

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Proto-oncogenes can be converted to oncogenes by

Movement of DNA within the genome: if it ends up near an active promoter, transcription may increase
Amplification of a proto-oncogene: increases the number of copies of the gene
Point mutations in the proto-oncogene or its control elements: causes an increase in gene expression

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Tumor-Suppressor Genes

Tumor-suppressor genes help prevent uncontrolled cell growth
Mutations that decrease protein products of tumor-suppressor genes may contribute to cancer onset
Tumor-suppressor proteins

Repair damaged DNA
Control cell adhesion
Inhibit the cell cycle in the cell-signaling pathway

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Interference with Normal Cell-Signaling Pathways

Mutations in the ras proto-oncogene and p53 tumor-suppressor gene are common in human cancers
Mutations in the ras gene can lead to production of a hyperactive Ras protein and increased cell division

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Fig. 18-21

Receptor

Growth

factor

G protein

GTP

Ras

GTP

Ras

Protein kinases

(phosphorylation

cascade)

Transcription

factor (activator)

DNA

Hyperactive

Ras protein

(product of

oncogene)

issues

signals

on its own

MUTATION

NUCLEUS

Gene expression

Protein that

stimulates

the cell cycle

(a) Cell cycle–stimulating pathway

MUTATION

Protein kinases

DNA

DNA damage

in genome

Defective or

missing

transcription

factor, such

as p53, cannot

activate

transcription

Protein that

inhibits

the cell cycle

Active

form

of p53

UV

light

(b) Cell cycle–inhibiting pathway

(c) Effects of mutations

EFFECTS OF MUTATIONS

Cell cycle not

inhibited

Protein absent

Increased cell

division

Protein

overexpressed

Cell cycle

overstimulated

1

2

3

4

5

2

1

3

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Fig. 18-21a

Receptor

Growth

factor

G protein

GTP

Ras

GTP

Ras

Protein kinases

(phosphorylation

cascade)

Transcription

factor (activator)

DNA

Hyperactive

Ras protein

(product of

oncogene)

issues

signals

on its own

MUTATION

NUCLEUS

Gene expression

Protein that

stimulates

the cell cycle

(a) Cell cycle–stimulating pathway

1

3

4

5

2

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Fig. 18-21b

MUTATION

Protein kinases

DNA

DNA damage

in genome

Defective or

missing

transcription

factor, such

as p53, cannot

activate

transcription

Protein that

inhibits

the cell cycle

Active

form

of p53

UV

light

(b) Cell cycle–inhibiting pathway

2

3

1

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Fig. 18-21c

(c) Effects of mutations

EFFECTS OF MUTATIONS

Cell cycle not

inhibited

Protein absent

Increased cell

division

Protein

overexpressed

Cell cycle

overstimulated

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Suppression of the cell cycle can be important in the case of damage to a cell’s DNA; p53 prevents a cell from passing on mutations due to DNA damage
Mutations in the p53 gene prevent suppression of the cell cycle

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The Multistep Model of Cancer Development

Multiple mutations are generally needed for full-fledged cancer; thus the incidence increases with age
At the DNA level, a cancerous cell is usually characterized by at least one active oncogene and the mutation of several tumor-suppressor genes

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Fig. 18-22

EFFECTS OF MUTATIONS

Malignant tumor

(carcinoma)

Colon

Colon wall

Loss of tumor-

suppressor gene

APC (or other)

Activation of

ras oncogene

Loss of

tumor-suppressor

gene DCC

Loss of

tumor-suppressor

gene p53

Additional

mutations

Larger benign

growth (adenoma)

Small benign

growth (polyp)

Normal colon

epithelial cells

5

4

2

3

1

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Fig. 18-22a

Colon

Colon wall

Normal colon

epithelial cells

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Fig. 18-22b

Loss of tumor-

suppressor gene

APC (or other)

Small benign

growth (polyp)

1

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Fig. 18-22c

Activation of

ras oncogene

Loss of

tumor-suppressor

gene DCC

Larger benign

growth (adenoma)

2

3

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Fig. 18-22d

Malignant tumor

(carcinoma)

Loss of

tumor-suppressor

gene p53

Additional

mutations

5

4

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Inherited Predisposition and Other Factors Contributing to Cancer

Individuals can inherit oncogenes or mutant alleles of tumor-suppressor genes
Inherited mutations in the tumor-suppressor gene adenomatous polyposis coli are common in individuals with colorectal cancer
Mutations in the BRCA1 or BRCA2 gene are found in at least half of inherited breast cancers

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Fig. 18-23

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Fig. 18-UN1

Operon

Promoter

Operator

Genes

RNA

polymerase

Polypeptides

A

B

C

B

A

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Fig. 18-UN2

Promoter

Genes

Genes not expressed

Inactive repressor:

no corepressor present

Corepressor

Active repressor:

corepressor bound

Genes expressed

Operator

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Fig. 18-UN3

Promoter

Genes

Genes not expressed

Active repressor:

no inducer present

Inactive repressor:

inducer bound

Genes expressed

Operator

Fig. 18-UN2

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Fig. 18-UN4

• Genes in highly compacted

chromatin are generally not

transcribed.

Chromatin modification

• DNA methylation generally

reduces transcription.

• Histone acetylation seems to

loosen chromatin structure,

enhancing transcription.

Chromatin modification

Transcription

RNA processing

Translation

mRNA

degradation

Protein processing

and degradation

mRNA degradation

• Each mRNA has a

characteristic life span,

determined in part by

sequences in the 5′ and

3′ UTRs.

• Protein processing and

degradation by proteasomes

are subject to regulation.

Protein processing and degradation

• Initiation of translation can be controlled

via regulation of initiation factors.

Translation

or

mRNA

Primary RNA

transcript

• Alternative RNA splicing:

RNA processing

• Coordinate regulation:

Enhancer for

liver-specific genes

Enhancer for

lens-specific genes

Bending of the DNA enables activators to

contact proteins at the promoter, initiating

transcription.

Transcription

• Regulation of transcription initiation:

DNA control elements bind specific

transcription factors.

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Fig. 18-UN5

Chromatin modification

RNA processing

Translation

mRNA

degradation

Protein processing

and degradation

mRNA degradation

• miRNA or siRNA can target specific mRNAs

for destruction.

• miRNA or siRNA can block the translation

of specific mRNAs.

Transcription

• Small RNAs can promote the formation of

heterochromatin in certain regions, blocking

transcription.

Chromatin modification

Translation

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Fig. 18-UN6

Enhancer

Promoter

Gene 3

Gene 4

Gene 5

Gene 2

Gene 1

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Fig. 18-UN7

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Fig. 18-UN8

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You should now be able to:

Explain the concept of an operon and the function of the operator, repressor, and corepressor
Explain the adaptive advantage of grouping bacterial genes into an operon
Explain how repressible and inducible operons differ and how those differences reflect differences in the pathways they control

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Explain how DNA methylation and histone acetylation affect chromatin structure and the regulation of transcription
Define control elements and explain how they influence transcription
Explain the role of promoters, enhancers, activators, and repressors in transcription control

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Explain how eukaryotic genes can be coordinately expressed
Describe the roles played by small RNAs on gene expression
Explain why determination precedes differentiation
Describe two sources of information that instruct a cell to express genes at the appropriate time

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Explain how maternal effect genes affect polarity and development in Drosophila embryos
Explain how mutations in tumor-suppressor genes can contribute to cancer
Describe the effects of mutations to the p53 and ras genes