Regulation of Gene

Expression
Chapter 18
 Gene expression
 Flow of genetic information
 Genotype to phenotype
 Genes to proteins
 Proteins not made at random
 Specific purposes
 Appropriate times
Control of gene expression
 Selective expression of genes
 All genes are not expressed at the
same time
 Expressed at different times
Prokaryote regulation
Control of gene expression
 Regulate at transcription
 Gene expression responds to
 Environmental conditions
 Type of nutrients
 Amounts of nutrients
 Rapid turn over of proteins
Fig. 18-2
Precursor
Feedback
inhibition
trpE gene

Enzyme 1

trpD gene
Regulation
of gene
expression
Enzyme 2 trpC gene

trpB gene

Enzyme 3

trpA gene

Tryptophan

(a) Regulation of enzyme (b) Regulation of enzyme

activity production
 Prokaryote
 Anabolism:
 Building up of a substance
 Catabolism:
 Breaking apart a substance
 Prokaryote
 Operon
 Section of DNA
 Enzyme-coding genes
 Promoter
 Operator
 Sequence of nucleotides
 Overlaps promoter site
 Controls RNA polymerase access to the
promoter
Figure 18.3a

DNA trp operon

Promoter
Promoter Regulatory gene
Genes of operon
trpR trpE trpD trpC trpB trpA
Operator
RNA
mRNA polymerase Start codon Stop codon
3′
mRNA 5′
5′

Protein
Inactive E D C B A
repressor
Polypeptide subunits that make up
enzymes for tryptophan synthesis
(a) Tryptophan absent, repressor inactive, operon on
 Prokaryote
 Multiple genes are expressed in a
single gene expression
 trp operon
– Trytophan
– Synthesis
 Lac operon
– Lactose
– Degradation
 Prokaryote
 trp Operon:
 Control system to make tryptophan
 Several genes that make tryptophan
 Regulatory region
Fig. 18-3a

trp operon
Promoter
Genes of operon
trpE trpD trpC trpB trpA
Operator
Start codon Stop codon

mRNA RNA mRNA 5

5 polymerase
E D C B A
Polypeptide subunits that make up
enzymes for tryptophan synthesis
 Prokaryote
 ⇧tryptophan present
 Bacteria will not make tryptophan
 Genes are not transcribed
 Enzymes will not be made
 Repression
 Prokaryote
 Repressors
 Proteins
 Bind regulatory sites (operator)
 Prevent RNA polymerase attaching
to promoter
 Prevent or decrease the initiation of
transcription
 Prokaryote
 Repressors
 Allosteric proteins
 Changes shape
 Active or inactive
 Prokaryote
 ⇧tryptophan
 Tryptophan binds the trp repressor
 Repressor changes shape
 Active shape
 Repressor fits DNA better
 Stops transcription
 Tryptophan is a corepressor
Fig. 18-3b-2

DNA
No RNA made

mRNA

Protein Active
repressor
Tryptophan
(corepressor)
(b) Tryptophan present, repressor active, operon off
 Prokaryote
 ⇩tryptophan
 Nothing binds the repressor
 Inactive shape
 RNA polymerase can transcribe
Fig. 18-3a

trp operon
Promoter Promoter
Genes of operon
DNA trpR trpE trpD trpC trpB trpA
Regulatory Operator
gene Start codon Stop codon
3
mRNA RNA mRNA 5
5 polymerase
E D C B A
Protein Inactive Polypeptide subunits that make up
repressor enzymes for tryptophan synthesis
(a) Tryptophan absent, repressor inactive, operon on
 Prokaryote
 Lactose
 Sugar used for energy
 Enzymes needed to break it down
 Lactose present
 Enzymes are synthesized
 Induced
 Prokaryote
 lac Operon
 Promoter
 Operator
 Genes to code for enzymes
 Metabolize (break down) lactose
 Prokaryote
 Lactose is present
 Repressor released
 Genes expressed
 Lactose absent
 Repressor binds DNA
 Stops transcription
 Prokaryote
 Allolactose:
 Binds repressor
 Repressor releases from DNA
 Inducer
 Transcription begins
 Lactose levels fall
 Allolactose released from repressor
 Repressor binds DNA blocks transcription
 Fig. 18-4b

lac operon

DNA lacI lacZ lacY lacA

RNA
polymerase
3
mRNA
mRNA 5
5

Protein - Permease Transacetylas

Galactosidase e

Allolactose Inactive
(inducer) repressor

(b) Lactose present, repressor inactive, operon on

Fig. 18-4a

Regulatory Promoter
gene
Operato
r
DNA lacI lacZ
No
RNA
made
3
mRNA RNA
5 polymerase

Active
Protein repressor

(a) Lactose absent, repressor active, operon off

 Prokaryote
 Lactose & tryptophan metabolism
 Adjustment by bacteria
 Regulates protein synthesis
 Response to environment
 Negative control of genes
 Operons turned off by active repressors
 Tryptophan repressible operon
 Lactose inducible operon
Prokaryote
 Prokaryote
 Activators:
 Bind DNA
 Stimulate transcription
 Involved in glucose metabolism
 lac operon
 Prokaryote
 Activator:
 Catabolite activator protein (CAP)
 Stimulates transcription of operons
 Code for enzymes to metabolize sugars
 cAMP helps CAP
 cAMP binds CAP to activate it
 CAP binds to DNA (lac Operon)
 Prokaryote
 Glucose elevated cAMP low
 cAMP not available to bind CAP
 Does not stimulate transcription
 Bacteria use glucose
 Preferred sugar over others.
 Prokaryote
 lac operon
 Regulated by positive & negative control
 Low lactose
 Repressor blocks transcription
 High lactose
 Allolactose binds repressor
 Transcription happens
 Prokaryote
 lac operon
 Glucose also present
 CAP unable to bind
 Transcription will proceed slowly
 Glucose absent
 CAP binds promoter
 Transcription goes quickly
Figure 18.5
Promoter
Operator
DNA
lac I lacZ

CAP-binding site RNA

polymerase
Active binds and
cAMP CAP transcribes

Inactive lac
Inactive repressor
CAP
Allolactose
(a) Lactose present, glucose scarce (cAMP level high):
abundant lac mRNA synthesized

Promoter
DNA
lac I lacZ

CAP-binding site Operator

RNA
polymerase less
likely to bind
Inactive
Inactive lac
CAP
repressor

(b) Lactose present, glucose present (cAMP level low):

little lac mRNA synthesized
Eukaryote gene expression
 All cells in an organism have the
same genes
 Some genes turned on
 Others remain off
 Leads to development of specialized
cells
 Cellular differentiation
Eukaryote gene expression
 Gene expression assists in regulating
development
 Homeostasis
 Changes in gene expression in one
cell helps entire organism
Control of gene expression
 Chromosome structure
 Transcriptional control
 Posttranscriptional control
Fig. 18-6 Signal

NUCLEUS
Chromatin

Chromatin
modification
DNA
Gene available
for transcription
Gene
Transcription
RNA Exon
Primary transcript
Intron
RNA processing
Tail

Cap mRNA in nucleus

Transport to cytoplasm

CYTOPLASM
mRNA in cytoplasm

Translatio
Degradation n
of mRNA

Polypeptide

Protein processing

Active protein
Degradation
of protein
Transport to cellular
destination

Cellular function
 Eukaryotes
 1. DNA is organized into chromatin
 2. Transcription occurs in nucleus
 3. Each gene has its own promoter
 Chromatin structure
 DNA is tightly packaged
 Heterochromatin:
 Tightly packed
 Euchromatin:
 Less tightly packed
 Influences gene expression
 Promoter location
 Modification of histones
 Chromatin structure
 Histone acetylation
 Acetyl groups (-COCH3)
 Attach to Lysines in histone tails
 Loosen packing
 Histone methylation
 Methyl groups (-CH3)
 Tightens packing
Fig. 18-7

Histone
tails

Amino
acids
available
DNA for chemical
double helix modification

(a) Histone tails protrude outward from a

nucleosome

Unacetylated histones Acetylated histones

(b) Acetylation of histone tails promotes loose

chromatin structure that permits transcription
 Chromatin structure
 Methylation of bases (cytosine)
 Represses transcription
 Embryo development
 Eukaryotes
 Epigenetic change:
 Chromatin modifications
 Change in gene expression
 Passed on to the next generation
 Not a DNA sequence change
 Transcription control
 RNA polymerase must bind DNA
 Proteins regulate by binding DNA
 RNA polymerase able to bind or not
 Stimulates transcription or blocks it
Fig. 18-8-3

Poly-A signal
sequence
Enhancer Proximal
Termination
(distal control elements) control elements region
Exon Intron Exon Intron Exon
DNA
Upstream Downstream
Promoter Transcription

Primary RNA Exon Intron Exon Intron Exon Cleaved 3 end

transcript 5 of primary
RNA processing transcript

Intron RNA Poly-A

signal
Coding segment
mRNA 3
Start Stop
5 Cap 5 UTR codon codon 3 UTR Poly-A
tail
 Eukaryotes
 Transcription
 RNA Polymerase
 Transcription factors (regulatory
proteins)
 General transcription factors
(initiation complex)
 Specific transcription factors
 Eukaryotes
 Initiation of transcription
 Activator proteins
 Activator binds the enhancers
 Enhancers (DNA sequences)
 Interacts with the transcription factors
 Binds to the promoter
 RNA polymerase binds and transcription
begins
Fig. 18-9-2
Activators Promoter
Gene
DNA
Enhancer Distal control TATA
element box
General
transcription
factors
DNA-bending
protein

Group of
mediator proteins
Fig. 18-9-3
Activators Promoter
Gene
DNA
Enhancer Distal control TATA
element box
General
transcription
factors
DNA-bending
protein

Group of
mediator proteins

RNA
polymerase II

RNA
polymerase II

Transcription
initiation complex RNA synthesis
Eukaryotes
Fig. 18-10
Enhancer Promoter

Control Albumin gene

elements

Crystallin gene

LIVER CELL LENS CELL

NUCLEUS NUCLEUS
Available
activators Available
activators

Albumin gene
not expressed
Albumin gene
expressed

Crystallin gene
not expressed
Crystallin gene
expressed
(a) Liver cell (b) Lens cell
Post transcriptional control
 RNA processing
 Primary transcript:
 Exact copy of the entire gene
 RNA splicing
 Introns removed from the mRNA
 snRNP’s (small nuclear
ribonulceoproteins)
Post transcriptional control
 Splicing plays a role in gene
expression
 Exons can be spliced together in
different ways.
 Leads to different polypeptides
 Originated from same gene
Post transcriptional control
 Example in humans
 Calcitonin & CGRP
 Hormones released from different
organs
 Derived from the same transcript
Fig. 18-11

Exons

DNA

Troponin T gene

Primary
RNA
transcript

RNA splicing

mRNA or
Post transcriptional control
Post transcriptional control
 Transport of transcript
 Passes through nuclear pores
 Active transport
 Cannot pass until all splicing is done
Post transcriptional control
 mRNA degradation
 Life span
 Some can last hours, a few weeks
 mRNA for hemoglobin survive awhile
Post transcriptional control
Post transcriptional control
 Translation of RNA
 Translation factors are necessary
 Regulate translation
 Translation repressor proteins
 Stop translation
 Bind transcript
 Prevents it from binding to the ribosome
Post transcriptional control
Post transcriptional control
 Ferritin (iron storage)
 Aconitase:
 Translation repressor protein
 Binds ferritin mRNA
 Iron will bind to aconitase
 Aconitase releases the mRNA
 Ferritin production increases
Post transcriptional control
 Protein modification
 Phosphorylation
 Other alterations can affect the
activity of protein
 Insulin
 Starts out as a larger molecule
 Cut into more active sections
Post transcriptional control
 Protein modification
 Degradation
 Protein is marked by small protein
 Protein complex then breaks down
proteins
 Proteasomes
Post transcriptional control
Post transcriptional control
Fig. 18-UN4
Chromatin modification Transcription

• Genes in highly compacted • Regulation of transcription initiation:

chromatin are generally not DNA control elements bind specific
transcribed. transcription factors.
• Histone acetylation seems to
loosen chromatin structure,
enhancing transcription.

Bending of the DNA enables activators to

• DNA methylation generally contact proteins at the promoter, initiating
reduces transcription. transcription.
• Coordinate regulation:
Enhancer for Enhancer for
liver-specific genes lens-specific genes

Chromatin modification

Transcription RNA processing

• Alternative RNA splicing:
RNA processing

Primary RNA
transcript
mRNA Translation
degradation mRNA or
Protein processing
and degradation
Translation
• Initiation of translation can be controlled
via regulation of initiation factors.
mRNA degradation
• Each mRNA has a
characteristic life span, Protein processing and degradation
determined in part by
sequences in the 5 and • Protein processing and
3 UTRs. degradation by proteasomes
are subject to regulation.
Post transcriptional control
 Most gene regulation-transcription
 New discovery
 Small RNA’s
 21-28 nucleotides long
 Play a role in gene expression
 New transcript before leaving the
nucleus
Post transcriptional control
 RNA interference
 RNA forming double stranded loops
from newly formed mRNA
 Loops are formed
 Halves have complementary sequences
 Loops inhibit expression of genes
 Where double RNA came from
Post transcriptional control
 Dicer:
 Cuts double stranded RNA into
smaller RNA’s called
 microRNA (miRNA)
 Small interfering RNA (siRNA’s)
Fig. 18-13

Hairpin miRNA Hydrogen

bond

Dicer

miRNA miRNA-
5 3 protein
(a) Primary miRNA transcript complex

mRNA degraded Translation blocked

(b) Generation and function of miRNAs
Post transcriptional control
 miRNA’s bind mRNA
 Prevents translation
 siRNA’s breaks apart mRNA before
it’s translated
Post transcriptional control
 siRNAs play a role in
heterochromatin formation
 Block large regions of the
chromosome
 Small RNAs may also block
transcription of specific genes
Fig. 18-UN5

Chromatin modification
Transcription
Chromatin modification
• Small RNAs can promote the formation of
heterochromatin in certain regions, blocking
transcription.

Translation
RNA processing
• miRNA or siRNA can block the translation
of specific mRNAs.
mRNA Translation
degradation

Protein processing
and degradation

mRNA degradation
• miRNA or siRNA can target specific mRNAs
for destruction.
 Embryonic development
 Zygote gives rise to many
different cell types
 Cells →tissues →
 organs → organ systems
 Gene expression
 Orchestrates developmental
programs of animals
Fig. 18-14a

(a) Fertilized eggs of a frog

 Embryonic development
 Zygote to adult results
 Cell division
 Cell differentiation:
 Cells become specialized in structure &
function
 Morphogenesis:
 “creation of from”
 Body arrangement
 Fig. 47-6

(a) Fertilized egg (b) Four-cell stage (c) Early blastula (d) Later blastula
Fig. 47-1

1 mm
 Fig. 46-17

(a) 5 weeks (b) 14 weeks (c) 20 weeks

 Embryonic development
 All cells same genome
 Differential gene expression
 Genes regulated differently in
each cell type
Fig. 18-10
Enhancer Promoter

Control Albumin gene

elements

Crystallin gene

LIVER CELL LENS CELL

NUCLEUS NUCLEUS
Available
activators Available
activators

Albumin gene
not expressed
Albumin gene
expressed

Crystallin gene
not expressed
Crystallin gene
expressed
(a) Liver cell (b) Lens cell
 Embryonic development
 Specific activators
 Materials in egg cytoplasm
 Not homogeneous
 Set up gene regulation
 Carried out as cells divide
 Embryonic development
 Cytoplasmic determinants
 Maternal substances in the egg
 Influence early development
 Zygote divides by mitosis
 Cells contain different cytoplasmic
determinants
 Leads to different gene expression
Fig. 18-15a
Unfertilized egg cell

Sperm Nucleus

Fertilization
Two different
cytoplasmic
determinants
Zygote

Mitotic
cell division

Two-celled
embryo

(a) Cytoplasmic determinants in the egg

 Embryonic development
 Environment around cell influences
development
 Induction:
 Signals from nearby embryonic cells
 Cause transcriptional changes in target
cells
 Interactions between cells induce
differentiation of specialized cell types
Fig. 18-15b

Early embryo NUCLEUS

(32 cells)

Signal
transduction
pathway

Signal
receptor

Signal
molecule
(inducer)

(b) Induction by nearby cells

 Embryonic development
 Determination:
 Observable differentiation of a cell
 Commits a cell to its final fate
 Cell differentiation is marked by the
production of tissue-specific proteins
 Gives cell characteristic structure &
function
 Embryonic development
 Myoblasts:
 Produce muscle-specific proteins
 Form skeletal muscle cells
 MyoD
 One of several “master regulatory
genes”
 Produces proteins
 Commit cells to becoming skeletal
muscle
 Embryonic development

 MyoD protein
 Transcription factor
 Binds to enhancers of various
target genes
 Causes expression
Fig. 18-16-1
Nucleus
Master regulatory gene myoD Other muscle-specific genes
DNA
Embryonic
precursor cell OFF OFF
Fig. 18-16-2
Nucleus
Master regulatory gene myoD Other muscle-specific genes
DNA
Embryonic
precursor cell OFF OFF

mRNA OFF

MyoD protein
Myoblast (transcription
(determined) factor)
Fig. 18-16-3
Nucleus
Master regulatory gene myoD Other muscle-specific genes
DNA
Embryonic
precursor cell OFF OFF

mRNA OFF

MyoD protein
Myoblast (transcription
(determined) factor)

mRNA mRNA mRNA mRNA

Myosin, other
muscle proteins,
MyoD Another and cell cycle–
Part of a muscle fiber transcription blocking proteins
(fully differentiated cell) factor
 Embryonic development
 Pattern formation:
 Development of spatial organization of
tissues & organs
 Begins with establishment of the major axes
 Positional information:
 Molecular cues control pattern formation
 Tells a cell its location relative to the body
axes & neighboring cells
Figure 18.24
1 Growth factor

3 G protein

P P NUCLEUS 6 Protein that

P P Ras 5
P P Transcription stimulates
GTP
factor (activator) the cell cycle

2 Receptor 4 Protein
kinases

MUTATION
Overexpression
Ras of protein
NUCLEUS
GTP
Transcription
factor (activator)
Ras protein active
with or without
growth factor.
Figure 18.25

2 Protein kinases

5 Protein that
inhibits the
NUCLEUS cell cycle
UV
light
1 DNA damage 3 Active form 4 Transcription
in genome of p53

Inhibitory
protein
UV absent
MUTATION Defective or
light
missing
DNA damage transcription
in genome factor.
 Fruit fly
 Unfertilized egg contains
cytoplasmic determinants
 Determines the axes before
fertilization
 After fertilization,
 Embryo develops into a segmented
larva with three larval stages
Fig. 18-17a

Head Thorax Abdomen

0.5 mm

Dorsal
Right
BODY Anterior Posterior
AXES Left
Ventral
(a) Adult
Fig. 18-17b
Follicle cell
1 Egg cell Nucleus
developing within
ovarian follicle Egg
cell
Nurse cell

2 Unfertilized egg Egg

shell
Depleted
nurse cells
Fertilization
Laying of egg

3 Fertilized egg

Embryonic
development

4 Segmented
embryo
0.1 mm
Body Hatching
segments

5 Larval stage

(b) Development from egg to larva

 Fruit fly
 Homeotic genes:
 Control pattern formation in late
embryo,larva and adult
 Fig. 18-18

Eye

Leg
Antenna

Wild type Mutant

 Fruit fly
 Maternal effect genes:
 Encode for cytoplasmic determinants
 Initially establish the axes of the body
of Drosophila
 Egg-polarity genes:
 Maternal effect genes
 Control orientation of the egg
 Consequently the fly
 Fruit Fly
 Bicoid gene
 Maternal effect gene
 Affects the front half of the body
 An embryo whose mother has a mutant
bicoid gene
 Lacks the front half of its body
 Duplicate posterior structures at both
ends
Fig. 18-19a
EXPERIMENT

Tail

Head

T1 T2 A8
T3 A7
A1 A2 A6
A3 A4 A5

Wild-type larva

Tail Tail

A8
A8 A7
A7 A6

Mutant larva (bicoid)