Download Ch. 11 The Control of Gene Expression (Lecture Notes)

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IV. Unit 4:
The Control of Gene Expression - Chapter 11
Two approaches are used to study development:
Recombinant DNA techniques are used to study the parts of gene regulation (Ch 12)
Trace the genetic causes of abnormal development as clues to how genes control normal development. This is
how Drosophila melanogaster mutants are studied.
11.1 In both eukaryotes and prokaryotes, cell specialization depends on the selective expression of genes.
Normally, cells are able to regulate the expression of genes so that only certain ones are fully turned on and
produce a protein product.
Turning on and off genes is the main way that gene expression is regulated.
Gene expression is the flow of genetic information from genotype to phenotype.
Single-celled organisms (including bacteria) go through metabolic changes during their lives and must turn on and
off gene activity to cause changes in their protein contents.
Cellular differentiation is the specialization in the structure and function of cells.
Thus, our earliest understanding of gene control came not from the study of eukaryotes, but from study of the
bacterium Escherichia coli.
11.2 Proteins interacting with DNA can turn genes on or off in response to environmental changes
The Operon Model
This model of gene control was first proposed as a hypothesis in 1961 by French biologists Francois Jacob and
Jacques Monod, for the control of lactose utilization enzymes in E. coli.
Bacterial DNA contains control regions (operons) whose sole purpose is to regulate the transcription of structural
genes that code for enzymes or other products.
Important features of the model:
1. An operon consists of several DNA sequences coding for different enzymes, all involved in the same cellular
process.
2. Expression of the operon is controlled as a unit.
3. Other DNA sequences in and near the operon control the operon’s expression.
4. The presence or absence of the enzyme’s substrate turns on or off the controls.
Operon expression normally starts with RNA polymerase binding at the promoter region (the first nongene region
of the operon) and moving along and transcribing each gene in the operon.
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When the lac operon is “turned off” a regulator gene (the gene that codes for the repressor protein) continues to
be transcribed and translated into repressor protein. The repressor protein binds with the operator region (
the short sequence of DNA where the repressor binds preventing RNA polymerase for attaching to the
promoter) of the operon, repressing the transcription of the genes further along the operon (structural
gene).
When the lac operon is “turned on” the regulator gene continues to be transcribed and translated into repressor,
but the presence of substrate (lactose) interferes with the binding of the repressor to the operator. This
permits the expression of the remainder of the operon (structural gene). Expression continues until the
substrate is used up. Then the repressor is free to repress the operator, and the operon turns off as above.
11.3 Operons come in several different varieties
The lac operon is repressed when lactose is absent and transcribed when lactose is present.
Another operon, the trp operon, is transcribed when tryptophan is absent and repressed when tryptophan is
present. The enzyme expressed by trp helps synthesize tryptophan.
A third type of operon uses activators rather than repressors. Activators are proteins produced by the regulatory
genes that make it easier for RNA polymerase to bind to the promoter region of an operon.
11.4 Differentiation produces a variety of specialized cells
Producing eukaryotic organelles and regulating their functions require a much more complex network of gene
control, even in single-celled protists.
In multicellular eukaryotes, there is the added complexity of regulating what kinds of cells are produced when and
where.
Muscle, nerve, sperm, and blood cells (and other cell types) of a single animal all are derived by repeated cell
divisions from the zygote.
The structure of each different cell type is visibly different, reflecting its function.
Control of gene expression occurs at four levels in eukaryotes. In the nucleus there is transcriptional and
posttransciptional control; in the cytoplasm there is translational and posttranslational control.
(11.8-11.12)
11.5 Specialized cells may retain all of their genetic potential
Experimental evidence supports the retention of all of a multicellular organism’s DNA in each of its differentiated
cells, in most cases.
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In the 1950s, American embryologists Robert Briggs and Thomas King transplanted nuclei from differentiated cells
lining a frog tadpole’s intestine to unfertilized, eucleated frog eggs. Many such treated eggs developed into
normal tadpoles.
In some naturally occurring situations, differentiated cells’ DNA may “dedifferentiate” to give rise to other cell
types.
Many animals (lizards, starfish) can regenerate lost parts from differentiated cells that remain nearby.
Many plants can regenerate completely from differentiated cells. Plant tissue culture on sterile culture media is
now used widely to produce hundreds or thousands of genetic clones of domestic plants.
In many cases, particularly in animals, differentiated cells do not normally dedifferentiate. For instance, most
animals lack the ability to regenerate whole bodies from single isolated cells.
Most evidence suggests that cellular differentiation does not involve changes to the DNA.
11.6 Each type of differentiated cell has a particular pattern of expressed genes
As a developing embryo undergoes successive cell divisions, different genes are active in different cells at different
times.
Some genes (for example, those involved in the glycolysis pathway) are active in all metabolizing cells.
Other genes are turned on in only one cell line (for example, the crystallin gene in lens cells)
11.7 DNA packing in eukaryotic chromosomes affects gene expression
The total DNA in a human cell’s 46 chromosomes would stretch 3 meters. (This amount of DNA is packed in cell
nuclei as small as 5 µm in diameter, a reduction factor of almost 1 million in scale)
All the DNA fits because of elaborate packing: wrapping around histones and other proteins into nucleosomes,
coiling, supercoiling, and additional folding into chromosomes.
DNA packing must control the expression of genes, but there is little experimental evidence of how this
happens.
An interesting known example of the role of DNA packing in the control of expression is the formation of Barr
bodies from X chromosomes in the cells of female mammalians.
Certain cell lines have one or the other X chromosomes (inherited from the individual’s mother or father)
condensed into an Barr body (heterochromatin) and thus turned off (no transcription can occur); there can
be a random mosaic of expression of these two X chromosomes, as is seen in calico cats. (sweat glands of
human females)
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11.8 Eukaryotic gene expression can be regulated at transcription
Giant chromosomes in the salivary glands of fruit-fly larvae contain hundreds of replicated copies of each DNA
strand.
At different times, different regions of these chromosomes “puff” or loop out, exposing parts of the DNA
(euchromatin).
These puffs correspond to regions of RNA synthesis, implying that just the puffs are being transcribed at the time.
Changes in puffing patterns can be induced by the application of molting hormone. This implies that systems
similar to those shown to function in operons in prokaryotes function to control eukaryotic gene expression.
Hypotheses suggest eukaryotic activator proteins help position RNA polymerase molecules on DNA promoter
regions.
11.9 Noncoding segments interrupt many eukaryotic genes
Structural compartmentalization of eukaryotes offers opportunities for the post-transcriptional control of gene
expression.
The noncoding stretches of eukaryotic genes are called introns, and the parts that are expressed are called exons.
Both introns and exons are transcribed. Before leaving the nucleus, the introns are removed from the mRNA
transcript, and the remaining exons are spliced together. (RNA splicing)
Introns have been shown to function in gene regulation in several ways. Some introns appear to include sequences
that function at the transcription level in gene regulation and are not needed to translate into protein
structure. In other cases, the remaining exons can be spliced in different ways, to provide a cell with
several possible products from one gene region.
Finally, it has been suggested that introns make genes longer, thereby increasing the possibility of crossovers
between exons, and providing another mechanism to increase genetic diversity.
11.10 Eukaryotic mRNA is capped, tailed, and sometimes edited
These action occur while the spliced (intron-less) mRNA is still in the nucleus.
Additions of cap and tail seem to help protect the mRNA from attack by cellular enzymes and may enhance
translation.
Editing of internal sequences (RNA editing) can almost double the length of the mRNA.
11.11 Gene expression is also controlled during and after translation
Translational controls directly affect whether an mRNA is translated and the amount of gene product
eventually produced.
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The lifetime of mRNA molecules varies, controlling the amount of protein translated from a single transcription
and post-transcriptional processing event. In nonmammalian vertebrates, red blood cells lose their nuclei,
but not their ribosomes and mRNAs, which can continue to translate into hemoglobin for a month or more.
Some inhibitory control of the process of translation is known, such as the inhibitory action of a protein found in
red blood cells when heme subunits are not available.
Posttranslational control affects the activity of a protein product, whether or not it is functional, and the
length of time it is functional.
Post-translation control mechanisms in eukaryotes often involve cutting polypeptides into smaller, active final
products.
Another post-translational control affects how fast protein products are degraded.
11.12 Review: Multiple mechanisms regulate gene expression in eukaryotes
11.13 Master control genes determine an animal’s overall body plan
Homeotic genes are master controls that function during embryonic development in animals to determine the
developmental fates of different groups of cells destined to become different tissues.
Their improper functioning can lead to bizarre changes in morphology.
In fruit flies, every homeotic gene examined contains a common sequence of 180 nucleotides (homeoboxes), and
these sequences are almost identical to similar sequences in other animals.
Presumably, homeotic proteins activate or repress gene transcription and regulate development by coordinating
batteries of development genes.
11.14 Growing out of control, cancer cells produce malignant tumors
In all its forms, cancer is a disease of gene expression.
Tumors are abnormal masses of cells starting from single cells that have lost some control over their continued
division.
Benign tumors are composed of cells that multiply excessively but remain in place.
Malignant tumors are composed of cells that spread into neighboring tissues, breaking up and potentially
spreading (metastasis) throughout the body.
Over 200 types of cancers are recognized in humans.
Carcinomas originate in body coverings.
Sarcomas arise in supporting tissues.
Leukemias and lymphomas are cancers of blood- and lymph- related tissues.
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Cancer cells differ from normal cells in the following ways:
Normal Cells
Cancer Cells
Controlled growth
Uncontrolled growth
Contact inhibition
No contact inhibition
One organized layer
Disorganized, multilayered
Differentiated cells
Nondifferentiated cells, Abnormal nuclei
11.15 Virus-induced genetic changes cause some forms of cancer
About 15% of human cancer cases are caused by cancer-inducing viruses.
Viruses linked to human cancers include hepatitis B virus and human papillomavirus (which causes genital warts)
When viral DNA is inserted into a cell’s DNA, it may carry cancer-causing genes.
11.16 Cancer results from mutations in somatic cells
Cancer-causing genes are known as oncogenes.
Research has identified about 60 proto-ongogenes in the chromosomes of many animals, including humans, that,
under the right conditions, can be converted to oncogenes.
Many of these genes normally provide code for some aspect of molecular control of cell division.
Three kinds of changes in a proto-oncogene in a somatic cell could lead to its becoming an oncogene:
1. mutation within the gene to change its expressed protein’s function:
2. formation of multiple copies of the gene, leading to too much
expressed protein; or
3. movement of the gene to another location where its expression is
controlled differently.
Tumor-suppressor genes normally inhibit the uncontrolled cell division. Their inactivation may contribute to
uncontrolled cell division.
Usually more than one change in the genes of a somatic cell is required for it to become cancerous. For example,
the development of colon cancer is gradual, paralleled at the molecular level by the activation of one
oncogene and the inactivation of two tumor-suppressor genes.
11.17 Changes in lifestyle can reduce the risk of cancer
Cancer-causing agents other than viruses are called carcinogens.
Mutagenic chemicals cause mutations. In general, mutagens are carcinogens.
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The largest group of carcinogens are mutagens. Substances from tobacco are known to cause more cases and types
of cancer than any other single agent.
Exposure to carcinogens is additive, so long-term exposure to these agents is more likely to cause cancer.
Tissues in which cells have high rates of cell division are more likely to become cancerous.
Many factors that expose a person to cancer-causing agents involve involuntary behaviors. But voluntary
behaviors, such as choosing to include more fiber in one’s diet, can lower the risk. There is much evidence
that the tendency to get certain cancers is hereditary. (genetic predisposition)
These behaviors help prevent cancer:
Don’t Smoke Cigarette smoking accounts for about 30% of all cancer deaths. Smoking is responsible for 90% of
lung cancer cases among men and 79% among women - about 87% altogether. Smokeless tobacco
(chewing tobacco or snuff) increases the risk of cancers of the mouth, larynx, throat, and esophagus.
Don’t Sunbathe Almost all cases of basal and squamous cell skin cancers are considered to be sun related.
Further sun exposure is a major factor in the development of melanoma, and the incidence of this cancer
increases for those living near the equator.
Avoid Alcohol Cancers of the mouth, throat, esophagus, larynx, and liver occur more frequently among drinkers,
especially when accompanied by tobacco use (cigarettes or chewing tobacco).
Avoid Radiation Excessive exposure to ionizing radiation can increase cancer risk. Even though most medical
and dental X-rays are adjusted to deliver the lowest dose possible, unnecessary X-rays should be
avoided.Excessive radon exposure in homes increases the risk of lung cancer.
Be Tested for Cancer Do the shower check for breast cancer or testicular cancer. Have other exams done
regularly be a physician.
Be Aware of Occupational Hazards Exposure to several different industrial agents (nickel, chromate, asbestos,
vinyl chloride, etc.) and/or radiation increases the risk of various cancers.
Be Aware of Hormone Therapy Estrogen therapy to control menopausal symptoms increases the risk of
endometrial cancer.
11.18 Are we genetically programmed to age?
Organisms continue to change after developing into reproductive adults.
The process of aging, and the average maximum age to which each species lives, are likely to be genetically
programmed.
Two (not necessarily mutually exclusive) hypotheses explain aging.
1. The cumulative effects of nonlethal mutations and other damage to cells cause them to lose function gradually.
2. Aging is an innate property of cells, brought on by the expression of specific genes or programmed changes that
affect all genes.