Control of Gene Expression
Consider
 Prokaryotes must be able to adjust to their changing environments
o
Sometimes the environment can change almost instantly
 Eukaryotes have to respond as well, although typically not as drastically
 With multicellular organisms, different types of cells express different sets of genes
 Structural genes encode proteins involved in metabolic or biosynthetic pathways or
that play some structural role in the cell
 Regulatory genes encode proteins involved in the control of gene expression of other
genes
 There are regulatory elements (sequences) in the DNA where regulatory proteins
will bind
Prokaryotic gene regulation
 One fundamental difference between prokaryotic and eukaryotic genomes is the
presence of operons in prokaryotes
 In operons, genes with related functions are present in tandem and under the same
transcriptional control
Components
 Regulator gene encodes the regulator protein
 The regulator protein usually binds to the operator
What type of control?
 Is the regulatory protein a repressor or an activator?
 Is the key molecule a substrate or a product?
Negative control
 The regulatory protein is a repressor
 Negative control can be either inducible or repressible
 Negative inducible operons
 Binding of the repressor inhibits transcription
 Binding of an inducer to the repressor inactivates the repressor, releasing the
inhibition
 The repressor is usually an allosteric protein
 Negative repressible operons
 The repressor protein is normally inactive, incapable of binding
 Binding of a corepressor activates the repressor
Positive control
 The regulatory protein is an activator
 Positive control can be either inducible or repressible
lac operon
 Consists of three structural genes
 lacZ (β-galactosidase), lacY (permease), and lacA (transacetylase)
o
These are coordinately inducible
 The analysis of various classes of mutants was crucial to understanding the lac
operon
But that is only part of the lac operon story ...
o Many bacteria will metabolize glucose before any other sugar, including lactose
o What happens when lactose and glucose are both present?
Catabolite repression
o The active catabolite activator protein (CAP) can bind upstream of the promoter to
increase transcription
o Activation of CAP requires cAMP binding
o [cAMP] is dependent upon [glucose]
o So high-level expression of the operon requires
1. Lactose (allolactose) present
2. Low [glucose]
trp operon
o Consists of five structural genes whose polypeptides account for three enzymes
important in tryptophan biosynthesis
o The trp operon exhibits repressible control for initiation of transcription ...
o but it also shows control over the continuation of transcription
Attenuation
o Premature termination of transcription can obviously affect expression as well
o The key is the long 5’ untranslated* region (5’ UTR)
o Regions 1 and 2 are complementary; regions 2 and 3 are complementary; and
regions 3 and 4 are complementary
Riboswitches
o The secondary structure of the 5’ portion of the mRNA can affect either transcription
or translation
Eukaryotic control of gene expression
o Since there are so many steps to gene expression, there are many possible
levels of control
o Each gene typically has its own promoter and regulatory regions
o Chromatin structure affects gene expression
o Activator proteins are more prevalent in eukaryotes
o When DNA is tightly coiled around histone proteins, transcription cannot
occur
o
A general relaxation of the DNA in the vicinity of the gene is
required for transcription to occur
o
Histone acetylation can destabilize the nucleosome structure
o
Some transcription factors have acetyltransferase activity
o
Deacetylation can restore chromatin repression
o
Other chemical modifications also have an effect
o
The SWI/SNF complex can cause chromosome remodeling in
several different ways
o
Methylation of cytosine bases (especially in the vicinity of
promoters) decreases expression
Eukaryotic control of transcription
o Cis-acting components
o Enhancers and silencers
o Core promoters can be either focused or dispersed
o
Focused promoters are prevalent in lower eukaryotes but less
common in vertebrates
o Components of the core promoters can vary
o
Others include the CAAT and GC boxes
o Multiple regulatory elements allow for coordinated expression of genes
o They also allow for fine-tuned expression of genes
o
The human metallothionein IIA gene is expressed in response to the
presence of heavy metals (e.g., zinc and cadmium) and steroid
hormones like glucocorticoids
o
The protein binds to the heavy metals to decrease their toxic effects
Eukaryotic control of transcription
o Components
o
Basal transcription apparatus
o
Activators
o
Coactivators
o
Repressors
o That accounts for basal level transcription
o The activators and coactivators are required for high level transcription
Posttranscriptional gene regulation is crucial in eukaryotes
o Alternative splicing can generate different mRNAs from the same pre-mRNAs
RNA silencing
o miRNAs and siRNAs play a role in regulating gene expression
Epigenetic changes
o Epigenetic modifications are chemical modifications that affect gene
expression by altering chromatin structure
o
They can be passed on to other cells or even future generations
o
We know how DNA methylation can be maintained through
chromosome replication
o
How other epigenetic marks (e.g., histone modifications,
nucleosome positioning) are maintained is unclear