Chapter 18
description
Transcript of Chapter 18
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Chapter 18
Regulation of
Gene Expression
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Regulation of Gene Expression
Important for cellular control and differentiation.
Understanding “expression” is a “hot” area in Biology.
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General Mechanisms
1. Regulate Gene Expression
2. Regulate Protein Activity
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Operon Model
Jacob and Monod (1961) - Prokaryotic model of gene control.
Always on the National AP Biology exam !
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Operon Structure
1. Regulatory Gene
2. Operon Area a. Promoter
b. Operator
c. Structural Genes
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Gene Structures
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Regulatory Gene
Makes Repressor Protein which may bind to the operator.
Repressor protein blocks transcription.
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Promoter
Attachment sequence on the DNA for RNA polymerase to start transcription.
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Operator
The "Switch”, binding site for Repressor Protein.
If blocked, will not permit RNA polymerase to pass, preventing transcription.
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Structural Genes
Make the enzymes for the metabolic pathway.
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Lac Operon
For digesting Lactose. Inducible Operon - only
works (on) when the substrate (lactose) is present.
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If no Lactose
Repressor binds to operator. Operon is "off”,
no transcription, no enzymes made
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If Lactose is absent
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If Lactose is present
Repressor binds to Lactose instead of operator.
Operon is "on”, transcription occurs, enzymes are made.
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If Lactose is present
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Enzymes
Digest Lactose. When enough Lactose is
digested, the Repressor can bind to the operator and switch the Operon "off”.
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Net Result
The cell only makes the Lactose digestive enzymes when the substrate is present, saving time and energy.
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Animation
http://www.biostudio.com/d_%20Lac%20Operon.htm
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trp Operon
Makes Tryptophan. Repressible Operon.
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If no Tryptophan
Repressor protein is inactive, Operon "on” Tryptophan made.
“Normal” state for the cell.
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Tryptophan absent
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If Tryptophan present
Repressor protein is active, Operon "off”, no transcription, no enzymes
Result - no Tryptophan made
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If Tryptophan present
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Repressible Operons
Are examples of Feedback Inhibition.
Result - keeps the substrate at a constant level.
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Positive Gene Regulation
Positive increase of the level of transcription.
Uses CAP - Catabolite Activator Protein
Uses cAMP as a secondary cell signal.
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CAP - Mechanism
Binds to cAMP. Complex binds to the
Promoter, helping RNA polymerase with transcription.
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Result
If the amount of glucose is low (as shown by cAMP) and lactose is present, the lac operon can kick into high gear.
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Eukaryotic Gene Regulation
Can occur at any stage between DNA and Protein.
Be prepared to talk about several mechanisms in some detail.
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Chromatin Structure
Histone Modifications DNA Methylation Epigenetic Inheritance
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Histone Acetylation
Attachment of acetyl groups (-COCH3) to AAs in histones.
Result - DNA held less tightly to the nucleosomes, more accessible for transcription.
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DNA Methylation
Addition of methyl groups (-CH3) to DNA bases.
Result - long-term shut-down of DNA transcription.
Ex: Barr bodies genomic imprinting
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Epigenetics
Another example of DNA methylation effecting the control of gene expression.
Long term control from generation to generation.
Tends to turn genes “off”.
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Do Identical Twins have Identical DNA?
Yes – at the early stages of their lives.
Later – methylation patterns change their DNA and they become less alike with age.
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Transcriptional Control Enhancers and Repressors Specific Transcription
Factors Result – affect the
transcription of DNA into mRNA
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Enhancers
Areas of DNA that increase transcription.
May be widely separated from the gene (usually upstream).
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Posttranscriptional Control
Alternative RNA Processing Ex - introns and exons
Can have choices on which exons to keep and which to discard.
Result – different mRNA and different proteins.
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Another Example
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Results
Bcl-XL – inhibits apoptosis
Bcl-XS – induces apoptosis
Two different and opposite effects!!
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DSCAM Gene
Found in fruit flies Has 100 potential splicing sites. Could produce 38,000 different
polypeptides Many of these polypeptides have
been found
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Commentary
Alternative Splicing is going to be a BIG topic in Biology.
About 60% of genes are estimated to have alternative splicing sites. (way to increase the number of our genes)
One “gene” does not equal one polypeptide (or RNA).
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Other post transcriptional control points
RNA Transport - moving the mRNA into the cytoplasm.
RNA Degradation - breaking down old mRNA.
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Translation Control
Regulated by the availability of initiation factors.
Availability of tRNAs, AAs and other protein synthesis factors. (review Chapter 17).
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Protein Processing and Degradation
Changes to the protein structure after translation.
Ex: Cleavage Modifications Activation Transport Degradation
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Protein Degradation
By Proteosomes using Ubiquitin to mark the protein.
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Noncoding RNA
Small RNA molecules that are not translated into protein.
Whole new area in gene regulation.
Ex - RNAi
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Types of RNA
MicroRNAs or miRNAs. RNA Interference or RNAi using
small interfering RNAs or siRNAs.
Both made from RNA molecule that is diced into double stranded (ds) segments.
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RNAi
siRNAs or miRNAs can interact with mRNA and destroy the mRNA or block transcription.
A high percentage of our DNA produces regulatory RNA.
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Morphogensis
The generation of body form is a prime example of gene expression control.
How do cells differentiate from a single celled zygote into a multi-cellular organism?
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Clues?
Some of the clues are already in the egg.
Cytoplasmic determinants – chemicals in the egg that signal embryo development.
Made by Maternal genes, not the embryo’s.
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Induction
Cell to cell signaling of neighboring cells gives position and clues to development of the embryo.
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Fruit Fly Studies
Have contributed a great deal of information on how an egg develops into an embryo and the embryo into the adult.
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Homeotic (Hox) Genes
Any of the “master” regulatory genes that control placement of the body parts.
Usually contain “homeobox” sequences of DNA (180 bases) that are highly conserved between organisms.
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Comment
Evolution is strongly tied to gene regulation. Why?
What happens if you mutate the homeotic genes?
Stay tuned for more “evo-devo” links in the future.
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When things go wrong
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Example case
Bicoid (two tailed) – gene that controls the development of a head area in fruit flies.
Gene produces a protein gradient across the embryo.
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Result
Head area develops where Bicoid protein levels are highest.
If no bicoid gradient – get two tails.
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Other Genes Control the development of
segments and the other axis of the body.
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Gene Expression and Cancer
Cancer - loss of the genetic control of cell division.
Balance between growth-stimulating pathway (accelerator) and growth-inhibiting pathway (brakes).
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Proto-oncogenes Normal genes for cell growth and
cell division factors. Genetic changes may turn them
into oncogenes (cancer genes). Ex: Gene Amplification,
Translocations, Transpositions, Point Mutations
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Proto-oncogenes
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Tumor-Suppressor Genes
Genes that inhibit cell division.
Ex - p53, p21
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Cancer Examples
RAS - a G protein. When mutated, causes an
increase in cell division by over-stimulating protein kinases.
Several mutations known.
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Cancer Examples
p53 - involved with several DNA repair genes and “checking” genes.
When damaged (e.g. cigarette smoke), can’t inhibit cell division or cause damaged cells to apoptose.
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Carcinogens
Agents that cause cancer. Ex: radiation, chemicals Most work by altering the
DNA, or interfering with control or repair mechanisms.
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Multistep Hypothesis
Cancer is the result of several control mechanisms breaking down (usually).
Ex: Colorectal Cancer requires 4 to 5 mutations before cancer starts.
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Colorectal Cancer
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News Flash
Severe damage to a chromosome that causes it to “shatter” can lead to immediate cancer.
Doesn’t always take a long time and multiple steps.
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Can Cancer be Inherited?
Cancer is caused by genetic changes but is not inherited.
However, oncogenes can be inherited.
Multistep model suggests that this puts a person “closer” to developing cancer.
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Example – BRAC1
BRAC1 is a tumor suppressor gene linked with breast cancer.
Normal BRAC1 – 2% risk. Abnormal BRAC1 – 60% risk. Runs in families. Some will
have breasts removed to avoid cancer risk.
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Homework Read Chapter 20 Lab – Gel Electrophoresis.
Lab report – 2/9 New Discussion Forum –
articles found under “labs”. Chapter 18 – Fri. 2/10 No broadcast Mon. 2/6
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Summary Know Operons Be able to discuss several
control mechanisms of gene expression.
Be familiar with gene expression and development of organisms.
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Summary How control of DNA can lead
to cancer.