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Regulation of Gene Expression

Ch. 18 -- Prezi skeleton by David Knuffke
by

Ms Schwinge

on 5 December 2016

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Transcript of Regulation of Gene Expression

Regulation of Gene Expression
Prokaryotes
Eukaryotes
Eukaryotes regulate gene expression (and therefore their metabolism) at every step of protein synthesis from pre-transcription to post-translation. In multicellular organisms gene expression is essential for cell specialization
Operons:
Inducible:
Repressible:
Positive Gene Regulation:
Precursor
Enzyme 1
Enzyme 2
Enzyme 3
-
-
Gene 1
Gene 2
Gene 3
Gene 4
Gene 5
Product
Inhibition of
enzyme activity
Inhibition of
transcription
When Lactose is absent:
The repressor protein
(made by the
LacI

gene)
is able to attach to the operator
RNA polymerase cannot transcribe the structural genes
(
LacZ
,
LacY
and
LacA
)
that the cell needs to be able to digest lactose, since it can not attach to the promoter.
This is how things remain in the cell as long as there is no lactose present.
When Lactose is present:
The inducer molecule
(
allolactose
, a form of lactose)
binds to the repressor protein.
This changes the shape of the repressor protein so that it cannot attach to the promoter.
RNA polymerase is then able to transcribe the structural genes that the cell needs to be able to digest lactose.
This is how things remain in the cell until lactose is digested
What kind of feedback?
When tryptophan is absent:
The repressor protein
(made by the
TrpR
gene)
is unable to attach to the operator

RNA polymerase can transcribe the structural genes
(
TrpE
,
TrpD
,
TrpC
,
TrpB
, &
TrpA
)
that the cell needs to be able to synthesize tryptophan.
This is how things remain in the cell as long as there is no tryptophan present.
When Tryptohan is present:
The corepressor molecule
(
tryptophan
)
binds to the repressor protein.
This changes the shape of the repressor protein so that it can attach to the promoter.
RNA polymerase can not transcribe the structural genes that the cell uses to synthesize tryptophan.
This is how things remain in the cell until tryptophan is no longer present.
What kind of feedback?
When Lactose is present and glucose is low:
Low glucose means the amount of cyclic AMP (cAMP) is high
cAMP binds to the Catabolite Activator Protein (CAP), activating it
The Activated cAMP/CAP complex increases the rate of transcription of the lac operon
(and ~100 other catabolic operons),
boosting the rate of transcription several fold.
When Glucose and Lactose are both present:
Normal glucose level means the amount of cyclic AMP (cAMP) is low
cAMP is not bound to CAP
CAP is inactive.
Very little lac structural gene transcription occurs.
What kind of feedback?
What kind of logic?
What kind of logic?
What kind of logic?
Big Question
Make sure you can:
Polyribosomes demonstrating the coupling of transcription and translation in prokaryotes:
Prokaryotic control of metabolism through control of transcription:
How is gene expression controlled?
Explain the structure and function of all expression control systems described in this presentation.

Compare and contrast the expression control systems utilized in prokaryotic and eukaryotic cells.

Relate prokaryotic expression control systems to prokaryotic cellular organization and feedback mechanisms.

Relate eukaryotic expression control systems to eukaryotic cellular organization and the decoupling of transcription and translation.
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
Natural selection has favored bacteria that produce only the products needed by that cell

In prokaryotes, transcription and translation happen simultaneously
(they are "coupled"). The lack of a nucleus makes this very efficient.

A cell can regulate the production of enzymes by feedback inhibition or by gene regulation
(they do this almost entirely by regulating transcription)
. Gene expression in bacteria is controlled by the
operon model
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
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
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)
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
2 Major Flavors:
Inducible
and
Repressible
Ex: The
Lac
Operon
(digests lactose)
A
repressible operon
is one that is usually on; binding of a repressor to the operator shuts off transcription
(an example is the trp operon)
Ex: The
Trp
Operon
(synthesizes tryptophan)
An
inducible operon
is one that is usually off; a molecule called an
inducer
inactivates the repressor and turns on transcription
The lac operon is an inducible operon and contains genes that code for enzymes used in the hydrolysis and metabolism of lactose

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
Some operons are also subject to positive control through a stimulatory protein, such as catabolite activator protein (CAP), an
activator
of transcription
Ex: The
CAP/cAMP
System
A way to increase the rate of transcription of an operon
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.
Gene expression is regulated at many stages, and
errors in gene expression can lead to diseases (including cancer)
Genes within highly packed heterochromatin are usually not expressed
Chemical modifications to histones and DNA of chromatin influence both chromatin structure and gene expression.
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 histone code hypothesis proposes that specific combinations of modifications help determine chromatin configuration and influence 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
Regulation of Chromosome Structure
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
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
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
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
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
Enhancers and Specific Transcription Factors
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
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
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
A particular combination of control elements can activate transcription only when the appropriate activator proteins are present
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
Combinatorial Control of Gene Activation
Transcription alone does not account for gene expression
Regulatory mechanisms can operate at various stages after transcription, and such mechanisms allow a cell to fine-tune gene expression rapidly in response to environmental changes
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
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, and its life span is determined in part by sequences in the leader and trailer regions
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)
mRNA
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
Non-coding RNA
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:
1.) mRNA translation
2.) chromatin configuration
MicroRNAs (miRNAs)
are small single-stranded RNA molecules that can bind to mRNA and degrade it or block its translation

The phenomenon of inhibition of gene expression by RNA molecules is called
RNA interference (RNAi)

RNAi is caused by
small interfering RNAs (siRNAs).
siRNAs play a role in heterochromatin formation and can block large regions of the chromosome

siRNAs and miRNAs are similar but form from different RNA precursors. siRNAs may also block transcription of specific genes

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

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 cell. Thus, interactions between cells induce differentiation of specialized cell types
Determination
commits a cell to its final fate; it precedes differentiation.
Cell differentiation is marked by the production of tissue-specific proteins.
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
Sequential Regulation of Gene Expression During Cellular Differentiation
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

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
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


Drosophila
Nüsslein-Volhard and Wieschaus studied segment formation in flies, and determined that genes direct the developmental process.

They created mutants, conducted breeding experiments, and looked for corresponding genes. They found 120 genes essential for normal segmentation, but their experiments were complicated by
embryonic lethals
, embryos with lethal mutations
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
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
The gradient hypothesis: gradients of substances called
morphogens
establish an embryo’s axes and other features
Cancer
The gene regulation systems that go wrong during cancer are the very same systems involved in embryonic development

Cancer can be caused by mutations to genes that regulate cell growth and division

Tumor viruses can cause cancer in animals including humans
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
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
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
Mutations in the
ras proto-onco
gene can lead to production of a hyperactive Ras protein and increased cell division
Suppression of the cell cycle can be important in the case of damage to a cell’s DNA;
p53 tumor-suppressor gene
prevents a cell from passing on mutations due to DNA damage
. This is why
mutations in the p53 gene prevent suppression of the cell cycle
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
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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