Download Fig 16.12a - McGraw Hill Higher Education

PowerPoint to accompany
Genetics: From Genes to
Genomes
Fourth Edition
Leland H. Hartwell, Leroy Hood,
Michael L. Goldberg, Ann E. Reynolds,
and Lee M. Silver
Prepared by Mary A. Bedell
University of Georgia
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PART V
How Genes Are Regulated
CHAPTER
Gene Regulation in
Eukaryotes
CHAPTER OUTLINE
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16.1 Overview of Eukaryotic Gene Regulation
16.2 Control of Transcription Initiation
16.3 Chromatin Structure and Epigenetic Effects
16.4 Regulation After Transcription
16.5 A Comprehensive Example: Sex Determination in Drosophila
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Overview of eukaryotic gene regulation
Eukaryotes use complex sets of interactions
• Regulated interactions of large networks of genes
• Each gene has multiple points of regulation
Themes of gene regulation in eukaryotes:
• Environmental adaptation in unicellular eukaryotes
• Maintenance of homeostasis in multicellular
eukaryotes
 Genes are turned on or off in the right place and time
 Differentiation and precise positioning of tissues and
organs during embryonic development
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Compared to prokaryotes, eukaryotes
have additional levels of complexity for
controlling gene expression
Eukaryotic genomes are larger than prokaryotic genomes
Chromatin structure in eukaryotes makes DNA unavailable
to transcription machinery
Additional RNA processing events occur in eukaryotes
In eukaryotes, transcription takes place in the nucleus and
translation takes place in the cytoplasm
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Key regulatory differences between
eukaryotes and prokaryotes
Table 16.1
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Multiple steps where
production of the
final gene product
can be regulated in
eukaryotes
Fig. 16.1
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Control of transcription initiation
Three types of RNA polymerases in eukaryotes
• RNA pol I – transcribes rRNA genes
• RNA pol II – transcribes all protein-coding genes
(mRNAs) and micro-RNAs
• RNA pol III – transcribes tRNA genes and some small
regulatory RNAs
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RNA polymerase II transcription
RNA pol II catalyzes synthesis of the primary transcript,
which is complementary to the template strand of the gene
Most RNA pol II transcripts undergo further processing to
generate mature mRNA
• RNA splicing – removes introns
• Addition of 5' GTP cap – protects RNA from
degradation
• Cleavage of 3' end and addition of 3' polyA tail
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cis-acting elements: promoters and enhancers
Promoters – usually directly adjacent to the gene
• Include transcription initiation site
A A
• Often have TATA box: TATA A
T T
• Allow basal level of transcription
Enhancers – can be
far away from gene
• Augment or repress the basal level of transcription
Fig. 16.2
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Use of reporter genes to identify promoters
and enhancers in eukaryotes
Examples of reporter genes used in eukaryotes
• lacZ gene (Ch 15), blue color when X-gal used
• Gene for "green fluorescent protein" (GFP)
Mutations in regulatory regions can be engineered and
tested for effects on expression
Fig. 16.3
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trans-acting factors interact with cis-acting
elements to control transcription initiation
Direct effects of
transcription factors:
• Through binding to
DNA
Indirect effect of
transcription factors:
• Through proteinprotein
interactions
Fig. 16.4
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Use of reporter genes to identify trans-acting
factors in transcriptional regulation
Fig. 16.5
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Basal transcription factors
Basal transcription factors assist the binding of RNA pol II
to promoters (see Fig 16.6)
Key components of basal factor complex:
• TATA box-binding protein (TBP)
 Bind to TATA box
 First of several proteins to assemble at promoter
• TBP-associated factors (TAFs)
 Bind to TBP assembled at TATA box
RNA pol II associates with basal complex and initiates basal
level of transcription
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Basal factors bind to promoters of all
protein-encoding genes
Ordered pathway of
assembly at promoter:
1. TBP binds to TATA box
2. TAFs bind to TBP
3. RNA pol II binds to TAFs
Fig. 16.6
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Activators are transcription factors that
bind to enhancers
Activators are responsible for much of the variation in
levels of transcription of different genes
Increase levels of transcription by interacting directly or
indirectly with basal factors at the promoter
• 3-dimensional complex of proteins and DNA (Fig. 16.7)
Mechanisms of activator effects on transcription
• Stimulate recruitment of basal factors and RNA pol II to
promoters
• Stimulate activity of basal factors already assembled
on promoters
• Facilitate changes in chromatin structure
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Binding of activators to enhancers
increases transcriptional levels
Low level transcription occurs
when only basal factors are
bound to promoter
When basal factors and
activators are bound to DNA,
rate of transcription increases
Fig. 16.7
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Domains within activators
Activator proteins have two functional domains
• Sequence-specific DNA binding domain (Fig 16.8)
 Binds to enhancer
• Transcription-activator domain
 Interacts with other transcriptional regulatory proteins
Some activators have a third domain (Fig 16.9)
• Responds to environmental signals
• Example - steroid hormone receptors
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DNA-binding domains of activator proteins
Interacts with major groove
of DNA
Specific amino acids have
high-affinity binding to
specific nucleotide sequence
The three best-characterized
motifs:
• Helix-loop-helix (HLH)
• Helix-turn-helix (HTH)
• Zinc finger
Fig. 16.8
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Steroid hormone receptors are activators only
in the presence of specific hormones
Steroid hormones don't bind to DNA but are coactivators of
steroid hormone receptors
 In the absence of hormone, these receptors cannot bind to
DNA and so cannot activate transcription
 In the presence of hormone, these receptors bind to
enhancers for specific genes and activate their expression
Fig. 16.9
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Many activators must form dimers to function
Homodimers: multimeric proteins
made of identical subunits
Heterodimers: multimeric proteins
made of nonidentical subunits
Examples - Fos and Jun, both have
leucine zippers
 Fos forms heterodimers with Jun, but
cannot form homodimers
 Jun can form homodimers
 Jun-Jun and Jun-Fos dimers bind to
the same enhancer sequence, but
have different affinities
Fig. 16.10
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Dimerization domains make up another class
of transcription factor domains
Dimerization domains are specialized for polypeptidepolypeptide interactions
Leucine zippers are a common dimerization motif in
eukaryotes
Amino acid sequence twirls
into an a helix with leucines
protruding at regular intervals
Fig. 16.11
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Repressor proteins suppress transcription
initiation through different mechanisms
Some repressors have no effect on basal transcription but
suppress the action of activators
• Compete with activator for the same enhancer (Fig
16.12a)
OR
• Block access of activator to an enhancer (Fig 16.12b)
Some repressors eliminate virtually all basal transcription
from a promoter
• Block RNA pol II access to promoter
OR
• Bind to sequences close to promoter or distant from
promoter
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Repressor proteins that act through
competition with an activator protein
Repressor binds to the same enhancer sequence as the
activator
• Has no effect on the basal transcription level
Fig. 16.12a
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Repressor proteins that act through
quenching an activator protein
Quenchers bind to the activator but do not bind to DNA
• Type I: Repressor blocks the DNA-binding domain
• Type II: Repressor blocks the activation domain
Fig. 16.12b
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The same transcription factor can play
different roles in different cells
Example: a2 repressor in yeast
• Determines mating type by
binding to enhancers of
certain genes
 In a haploids and a/a
diploids, a2 binds to
enhancers of a-specific
genes but not to enhancers
of haploid-specific genes
Fig. 16.13
 In a/a diploids, binding
specificity of a2 is altered so
that it can bind to enhancers
of haploid-specific genes
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The Myc-Max mechanism can activate or
repress transcription
Myc − identified as an oncogene
• Regulates transcription of genes involved in cell
proliferation
• Doesn't have DNA binding activity on its own
Max − identified through its binding to Myc
• Max/Max homodimers and Myc/Max heterodimers bind
to the same enhancers
• Max/Max represses transcription
• Myc/Max activates transcription
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Comparative structures of Myc and Max
Myc/Myc homodimers cannot form
Max/Max homodimers and Myc/Max heterodimers can form
Max/Max homodimers bind DNA but cannot act as
activators
Fig. 16.14
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Dimer structure and subunit concentrations of
Myc and Max affect activation or repression
Max is constitutively expressed but Myc expression is
tightly regulated
Max/Max acts as a repressor when Myc is not expressed
Fig. 16.15a
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Dimer structure and subunit concentrations of
Myc and Max affect activation or repression
When Myc is present, Myc/Max heterodimers form and
activate transcription
• Myc - Max affinity is higher than Max - Max affinity
Fig. 16.15b
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Complex regulatory regions enable
fine-tuning of gene expression
Each gene can have many regulatory proteins
• In humans, ~2000 genes encode transcriptional
regulatory proteins
• Each regulatory protein can act on many genes
• Each regulatory region can have dozens of enhancers
Enhanceosome – multimeric complex of proteins and other
small molecules that associate with an enhancer
• Enhancers can be bound by activators and repressors
with varying affinities
• Different sets of cofactors and corepressors compete
for binding to activators and repressors
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Different enhancers for the string gene in
Drosophila are used in different cell types
Cells in different
parts of Drosophila
embryos go through
the 14th mitosis at
different times
The string gene
product activates
the 14th mitosis
Different activators
for string are
expressed at
different times in
different tissues
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Fig. 16.16
31
Chromatin structure and epigenetic effects
Chromatin structure can affect transcription
• Nucleosomes can sequester promoters and make them
inaccessible to RNA polymerase and transcription
factors
• Histone modification and DNA methylation
• Chromatin remodeling and hypercondensation
Epigenetic changes – changes in chromatin structure that
are inherited from one generation to the next
• DNA sequence is not altered
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Chromatin reduces transcription
Fig. 16.17
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Effects of chromatin structure on transcription:
Histone modification and DNA methylation
N-terminal tails of histones H3 and H4 can be modified
• Methylation, acetylation, phosphorylation, and
ubiquitination
• Can affect nucleosome interaction with other
nucleosomes and with regulatory proteins
• Can affect higher-order chromatin structure
DNA methylation occurs at C5 of cytosine in a CpG
dinucleotide
• Associated with gene silencing
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Determining methylation state of DNA using
two restriction enzymes and Southern blotting
HpaII and MspI have the same recognition sequence (CCGG),
but different sensitivity to DNA methylation
HpaII doesn't cut if
2nd C is methylated
Methylation doesn't
affect MspI cutting
Fig. 16.18
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Chromatin remodeling can
expose the promoter
Nucleosomes can be repositioned of removed by chromatin
remodeling complexes
• After remodeling, DNA at promoters and enhancers
becomes more accessible to transcription factors
• Can be assayed using DNase digestion (DNase
hypersensitive sites)
Fig. 16.19
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The SWl-SNF remodeling complex
One of best-studied remodeling complexes
Uses energy from ATP hydrolysis to alter nucleosome
positioning
Fig. 16.20
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Hypercondensation of chromatin results in
silencing of transcription
Examples of heterochromatin – inactive X chromosome,
centromeres, telomeres
Heterochromatin has methylation of CpG dinucleotides and
methylation of lysine in histone H3 tails
Fig. 16.21
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Gene silencing by the SIR complex in yeast
Gene for a2 repressor is at the MAT (mating type) locus
HML and HMR are copies of MAT locus but are silenced by
SIR complex
SIR mutations cause
sterility because
HML and HMR genes
not silenced and
both a- and aspecific genes are
expressed
Fig. 16.22
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Genomic imprinting results from
transcriptional silencing
Genomic imprinting – expression of a gene depends on
whether it was inherited from the mother or father
• Occurs with some genes of mammals
• Epigenetic effect (no change in DNA sequence)
Paternally imprinted gene is transcriptionally silenced if it
was transmitted from the father
• Maternal allele is expressed
Maternally imprinted gene is transcriptionally silenced if it
was transmitted from the mother
• Paternal allele is expressed
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In mice, deletion of Igf2 causes a mutant
phenotype only when transmitted by father
Maternal imprinting of Igf2 gene
• Maternally-inherited Igf2 allele is silenced
 Igf2 deletion heterozygotes have normal phenotype if the
mutant allele was inherited from the mother
Fig. 16.23a
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Methylation of complementary strands
of DNA in genomic imprinting
Epigenetic state can be
maintained across cell
generations through the
action of DNA methylases
Fig. 16.23b
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Insulators limit the chromatin region over
which an enhancer can operate
An insulator that binds CTCF is involved in reciprocal
imprinting of the Igf2 and H19 genes
Methylation of the
H19 promoter and
the insulator occurs
in spermatogenesis
A methylase is
essential for
imprinting of the
H19 gene
Fig.16.23c
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The resetting of
genomic imprints
during meiosis
Epigenetic imprints remain
throughout the lifespan of the
mammal
In germ cells, epigenetic
imprints are reset at each
generation
During meiosis, imprints are
erased and new ones are set
Fig. 16.23d
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Genomic imprinting and human disease
Examples: two syndromes associated with small deletions
in chromosome 15
• At least two genes within this region are differently
imprinted
• Praeder-Willi syndrome occurs when the deletion is
inherited from the father
• Angelman syndrome occurs when the deletion is
inherited from the mother
• Affected individuals have mental retardation and
development disorders
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Inheritance patterns of disorders resulting
from mutations in imprinted genes
These pedigrees may appear to be instances of incomplete
penetrance, but are distinctly different
Fig.
16.23e
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Regulation after transcription
Posttranscriptional regulation can occur at any step
At the level of RNA
• Splicing, stability, and localization
• Example – alternative splicing of mRNA
 Generates more diversity of proteins
 Common feature in eukaryotes
At the level of protein
• Synthesis, stability, and localization
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Expression of the Sxl mRNA in early
Drosophila development
Sex lethal (Sxl) gene encodes a protein required for femalespecific development (see Comprehensive example)
In early embryos, Sxl is transcribed only in females
Fig. 16.24a
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Differential RNA splicing of Sxl mRNA during
Drosophila development
Later in development, Sxl gene is transcribed in both sexes
Sxl protein regulates alternative splicing of its own mRNA
Fig. 16.24b
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Some small RNAs are responsible for
RNA interference (RNAi)
Specialized RNAs that prevent expression of specific genes
through complementary base pairing
• Small (21 – 30 nt) RNAs
• Micro-RNAs (miRNAs) and small interfering RNAs
(siRNAs)
 First miRNAs (lin-4 and let-7) identified in C. elegans
 Nobel prize to A. Fire and C. Mello in 2006
Posttranscriptional mechanisms for gene regulation
• mRNA stability and translation
• May also affect chromatin structure
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Primary transcripts containing miRNA
Most miRNAs are transcribed by RNA polymerase II from
noncoding DNA regions that generate short dsRNA hairpins
Fig. 16.25a
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miRNA processing
Drosha excises stem-loop from primary miRNA (pri-miRNA)
to generate pre-miRNA of ~ 70 nt
Dicer processes pre-miRNA to a mature duplex miRNA
One strand is incorporated into miRNA-induced silencing
complex (RISC)
Fig. 16.26
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Two ways that miRNAs can down-regulate
expression of target genes
When complementarity is
perfect:
When complementarity is imperfect:
•Target mRNA is degraded
repressed
•Translation of mRNA target is
Fig. 16.27
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siRNAs detect and destroy foreign dsRNAs
Two biological sources of dsRNAs that are precursors of
siRNAs (pri-RNAs)
• Transcription of both strands of an endogenous
genomic sequence
• Arise from exogenous virus
• pri-RNAs are processed by Dicer
• siRNA pathway targets dsRNAs for degradation
siRNAs are very useful experimental tools to selectively
knock down expression of target genes
• To study function of a gene, dsRNAs for that gene can
be introduced into cells
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Posttranslational modifications of proteins
Ubiquitination – covalent attachment of ubiquitin to other
proteins targets those proteins for degradation by the
proteosome
Cascades of phosphorylation and dephosphorylation
• Transmission of signals across the cell membrane to
the nucleus (discussed more in Chapter 17)
• Sensitization – tissues exposed to hormones for long
periods of time lose ability to respond to the hormone
 Example: binding of epinephrine to β-adrenergic receptors
on surface of heart muscle cells (see Fig 16.28)
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Phosphorylation and
desensitization of
β-adrenergic receptor
Phosphorylation of
receptor has no effect on
its binding to epinephrine,
but blocks its downstream
functions
Fig. 16.28
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Computer analyses can reveal
regulatory mechanisms
Can translate open reading frames into in silico proteins
Recognize motifs within proteins
• e.g. Zinc-finger domains or sites for posttranslational
modification
Phlyogenetic footprinting – compare noncoding DNA
sequences of closely related species
• Sequences that are conserved may have important
functions in gene regulation
ChIP technology – see Chapter 10
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A comprehensive example of gene regulation:
Sex determination in Drosophila
In Drosophila, ratio of X chromosomes to autosomal
chromosomes (X:A ratio) determines sex, fertility, and
viability
X:A ratio influences sex through three independent
pathways:
• Male vs female appearance and behavior
• Development of germ cells as eggs or sperm
• Dosage compensation – males have increased
transcription of X-linked genes
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Sex-specific traits in Drosophila
Fig. 16.29
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How chromosomal constitution affects
phenotype in Drosophila
Table 16.2
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Drosophila mutations that affect
the two sexes differently
Table 16.3
*Sxfl is a recessive mutation of Sex lethal
**SxlML is a dominant mutation of Sex lethal
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The X:A ratio regulates
transcription of the
Sxl gene
Several HLH transcription
factors are key regulators of sex
determination
• X-linked genes are
"numerator elements"
• Autosomal genes are
"denominator elements"
Numerator/denominator
determines ratio of HLH
homodimers and heterodimers
Only the homodimer activates
transcription of Sxl
Fig. 16.30
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The Sxl protein triggers a cascade of splicing of
transformer (tra) and double-sex (dsx) mRNAs
Sxl protein regulates
splicing of tra mRNA
Tra protein regulates
splicing of dsx mRNA
Fig. 16.31
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Dsx-F is a transcriptional activator and
Dsx-M is a transcriptional repressor
Fig.
16.32
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The Tra protein regulates splicing of
fruitless (fru) mRNA
Fig.
16.33
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