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Chapter 13

Terms in this set (50)

gene regulation
refers to the ability of cells to control their level of gene expression

majority of genes regulated to ensure that proteins are produced at the correct time and amount

saves energy by producing only when needed

constitutive genes are unregulated and have essentially constant levels of expression
prokaryotic gene regulation
Responds to changes in the environment

ex: Escherichia coli and lactose
-When lactose is available, two proteins are made:

lactose permease - transports lactose into the cell

β-galactosidase - breaks down lactose

-When lactose levels drop, the proteins are no longer made
gene regulation in eukaryotes
Necessary to produce different cell types in an organism - cell differentiation

All of the organism's cells contain the same genome but express different proteomes due to gene regulation
-Different proteins
-Different amounts of the same protein
developmental gene regulation in mammals
ex: Hemoglobin in fetal vs. adult humans

Fetal human stage characterized by continued refinement of body parts and a large increase in size

Gene regulation determines which globin polypeptides are made to become functional hemoglobin

Fetal hemoglobin has a higher affinity for oxygen than adult hemoglobin

Helps fetus to harvest oxygen from maternal blood
regulation of genetic expression
Most genes are expressed at all times

Other genes transcribed and translated when cells need them
-Allows cell to conserve energy

Regulation of polypeptide synthesis
-Typically halts transcription
-Can stop translation directly
bacterial gene regulation
Most commonly occurs at the level of transcription

Also can control rate of translation

Can be regulated at protein or post-translation level
eukaryotic gene regulation
-Transcriptional regulation common
-RNA processing
-Translation
-Post-translation
regulation of transcription in bacteria
Involves regulatory transcription factors

Bind to DNA in the vicinity of a promoter and affect transcription of one or more nearby genes

Repressors inhibit transcription
-Negative control
-Keep it off or turn it off, usually by blocking

Activators increase the rate of transcription
-Positive control
Transcriptional regulation also involves..
small effector molecules

binds to regulatory transcription factor and causes conformational change

determines whether or not regulatory transcription factor can bind to DNA
Two domains in regulatory transcription factor that respond to small effector molecules:
-Site where protein binds to DNA

-Site specifically for small effector molecule
operon
how BACTERIA can control gene expression

operon in bacteria is a cluster of genes under transcriptional control of one promoter
-Regulatory region called operator

Transcribed into mRNA as polycistronic mRNA

Allows coordinated regulation of a group of genes with a common function
nature of prokaryotic operons
an operon consists of a promoter and a series of genes

controlled by a regulatory element called an operator
regulation of protein synthesis and metabolism
genes are regulated to be active only when their products are required

in prokaryotes this regulation is coordinated by operons, a set of genes, all of which are regulated as a single unit
2 types of operons:
inducible

repressible
inducible operons
operon is turned ON by substrate: catabolic operons- enzymes needed to metabolize a nutrient are produced when needed
repressible operons
genes in a series are turned OFF by the product synthesized; anabolic operon- enzymes used to synthesize an amino acid stop being produced when they are not needed
lac operon
in E. coli contains genes for lactose metabolism

lac P- lac prooter

three structural genes:
lacZ- B galactosidase
lacY- lactose permease
lacA- galactosidase transacetylase

normally off. In the absence of lactose, the repressor binds with the operator locus and blocks transcription of downstream structural genes
when lactose is absent
lac repressor protein binds to nucleotides of the lac operator site preventing RNA polymerase from transcribing lacZ, lacY and lacA

RNA polymerase can bind but not move forward
when lactose is present
allolactose is a small effector molecule- 4 molecules bind to lac repressor to prevent it from binding DNA

process is induction- the lac operon is "Inducible"
when both lactose and glucose are high
the lac operon is shut off
-bacterium uses one sugar at a time, glucose
when lactose is high and glucose is low
the lac operon is turned on
-allolactose levels rise and prevent lac repressor from binding to operator
-bacterium uses lactose
when lactose is low and glucose is high or low
the lac operon is shut off
-under low lactose conditions, lac repressor prevents transcription of lac operon
trp operon
In E. coli, encodes enzymes required to make amino acid tryptophan

Regulated by a repressor protein encoded by trpR gene

Binding of repressor to trp operator site inhibits transcription

When tryptophan levels low, trp repressor cannot bind to operator site and operon genes transcribed

When tryptophan levels are high, tryptophan turns off the trp operon

Tryptophan acts as a small repressor molecule or corepressor
lac repressor binds to its operator in the absence of its small effector molecule
-Inducible: allolactose induces transcription

-operons for catabolism are often inducible

-genes turned off unless appropriate substance available
trp repressor binds to its operator only in the presence of its small effector molecules
-repressible: tryptophan represses transcription

-operons for anabolism are often repressible

-when enough of product present, genes are turned off to prevent overproduction
regulation of transcription in eukaryotes: roles of transcription factors and mediator
some of same principles as in prokaryotes:
-Activator and repressor proteins influence ability of RNA polymerase to initiate transcription
-Many regulated by small effector molecules

many important differences:
-genes almost always organized individually
-regulation more intricate
combinatorial control
1. Activators
2. Repressors
3. Modulation
4. Chromatin
5. DNA methylation
Activators
activator proteins stimulate RNA polymerase to initiate transcription
Repressors
repressor proteins inhibit RNA polymerase from initiating transcription
Modulation
small effector molecules, protein-protein interactions, and covalent modifications can modulate activators and repressors
Chromatin
activator proteins promote loosening up of the region in the chromosome where a gene is located, making it easier for RNA polymerase to transcribe the gene
DNA methylation
usually inhibits transcription, either by blocking an activator protein or by recruiting proteins that make DNA more compact

DNA methylase attaches methyl groups

Common in some eukaryotes but not all

In mammals, 5% of DNA is methylated

Usually inhibits transcription

CpG islands near promoters in vertebrates and plants
-Cytosine and guanine connected by phosphodiester bonds
-Unmethylated CpG islands are correlated with active genes
-Repressed genes contain methylated CpG islands
Three features of most promoters:
TATA box

Transcriptional start site

Regulatory or response elements
TATA box
5' -TATAAAA- 3'

25 base pairs upstream from transcriptional start site

Determines precise starting point for transcription
Transcriptional start site
where transcription begins

with TATA box forms core promoter
-by itself results in low level basal transcription
Regulatory or response elements
-Recognized by regulatory proteins that control initiation of transcription

-enhancers and silencers
Three proteins mediate transcription:
1. an RNA polymerase 2
2. 5 different general transcription factors (GTFs)
3. Large protein complex called mediator
Transcriptional regulation
activators- bind to DNA regions called enhancers

repressors- bind to DNA regions called silencers

regulate rate of transcription of a nearby gene

most do not bind directly to RNA polymerase 2
3 ways to control RNA polymerase 2
Activators and repressors regulate RNA polymerase II by binding to GTFs (including TFIID)

Regulate RNA polymerase II via mediator
-Activators stimulate mediator by allowing faster initiation
-Repressors inhibit mediator so RNA polymerase II cannot progress to elongation

Recruit proteins that influence DNA packing
regulation of transcription in eukaryotes: changes in chromatin structure and DNA methylation
DNA is associated with proteins to form compact chromatin

Chromatin packing affects gene expression

Transcription is difficult or impossible in the closed conformation of tightly packed chromatin

Access to the DNA is allowed in the loosely packed open conformation

Some activators diminish DNA compaction near a gene

Recruit proteins to loosen DNA compaction
-Histone acetyltransferase attaches acetyl groups to histone proteins so they don't bind DNA as tightly
-ATP-dependent chromatin remodeling enzymes also loosen DNA compaction
Histone code
many different amino acids in the amino terminal tails of histone proteins subject to several types of covalent modification

pattern of modifications (histone code) affects degree of chromatin compaction
nucleosome-free regions
-A nucleosome-free region (NFR) is found at the beginning and end of many genes

-Less regular distribution elsewhere
Methylation can inhibit transcription two ways:
1. The methylation of CpG islands may prevent an activator from binding to an enhancer elements

2. Converting chromatin from an open to a closed conformation
-Methyl-CpG-binding proteins bind to methylated sequences and recruit proteins that condense the chromatin
Regulation of RNA processing and translation in eukaryotes
Unlike bacteria, gene expression is commonly regulated at the level of RNA processing and translation

Added benefits include...
-Produce more than one mRNA transcript from a single gene (gene encodes 2 or more polypeptides)
-Faster regulation achieved by controlling steps after RNA transcript made
Alternative splicing of pre-mRNAs
In eukaryotes, a pre-mRNA transcript is processed before it becomes a mature mRNA

When a pre-mRNA has multiple introns and exons, splicing may occur in more than one way

Alternative splicing causes mRNAs to contain different patterns of exons.

Allows same gene to make different proteins
-At different stages of development
-In different cell types
-In response to a change in the environmental conditions

Linear order of exons is maintained in both alternates

Products usually have similar functions, because most of the amino acid sequence will be the same

Alternative splicing produces proteins with specialized characteristics

Advantage of alternative splicing:
-Different polypeptides from a single gene
-Bigger proteome with the same size genome
alternative splicing tends to be more prevalent in complex eukaryotic species
Alternative splicing increases the proteome size without increasing the total number of genes

For organisms to become more complex, as in higher plants and animals, evolution has produced more complex proteomes

General trend is that less complex organisms tend to have fewer genes

Frequency of alternative splicing increases with more biological complexity
microRNAs
miRNAs are small RNA molecules that silence the expression of pre-existing mRNAs
-Formerly known as small or short interfering RNA (siRNA)

Widely found in animals and plants

Important mechanism of mRNA silencing

Effect also called RNA interference (RNAi)

Synthesized as pre-miRNA

Cut by dicer to release miRNA

Associates with cellular proteins to become RNA-induced silencing complex (RISC)

Upon binding, either
-mRNA degraded
-Or, RISC inhibits translation

Either way, mRNA is silenced
iron toxicity in mammals
Another way to regulate translation involves RNA-binding proteins that directly affect translational initiation

Iron is a vital cofactor for many cellular enzymes

However, it is toxic at high levels

To prevent toxicity, mammalian cells synthesize a protein called ferritin, which forms a hollow, spherical complex that can store excess iron

mRNA that encodes ferritin is controlled by an RNA binding protein known as iron regulatory protein (IRP)
when iron in cytosol is low and ferritin is not needed,
IRP binds to a response element within the ferritin mRNA known as the iron regulatory element (IRE)

-Binding of IRP to the IRE inhibits translation of the ferritin mRNA
when iron is abundant in the cytosol
the iron binds directly to IRP and prevents it from binding to the IRE

-Ferritin mRNA is translated to make more ferritin protein

Faster than transcriptional regulation, which would require gene activation and transcription prior to the synthesis of more ferritin protein
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