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Gene Regulation Mechanisms

Mary A. Petti and Susan Terry
1994 Woodrow Wilson Collection


Introduction:

The study of genetics must include a discussion of how the chromosome and/or genes are regulated during the life of an organism. After investigating disease processes that affect the mechanism of a specific gene and studying the ways in which those changes might occur, the student should wonder, "How does the DNA do this?"

Molecular control of the genome may be studied at two basic levels. The prokaryotic model has been defined and many hands-on activities exist to explore the positive and negative feedback mechanisms. (See transformation labs) However, the eukaryotic model is very complex and many parts of it have not been defined.

Advanced placement students are expected to have an understanding of the developmental process which involves the determination and differentiation of the zygote as it moves from fertilization, cleavage, blastula formation and germ layer development. This complex process, that underlies the distinction between organisms, is controlled by the selective expression of genes.

The complexity of this genomic regulation may be simplified by the use of the following teaching sequence:

  1. Compare and contrast the genomic regulation of prokaryotic and eukaryotic cells using manipulatives.

  2. Use labs and/or examples of disease processes to illustrate the mutation related to these regulatory mechanisms. (See below)

  3. Complete a fertilization lab or study which illustrates differential developmental embryology. (Sea urchin lab example below)

  4. Culminate this genomic regulation unit with discussion questions that require the synthesis of DNA regulation mechanisms with actual developmental events.

Part I and II: Model Manipulation and Examples

Background Information: Control of Gene Expression in Eukaryotes

A. Transcriptional control

DNA packing, DNA methylation, chromosome puffs, promoter and enhancer regions

B. Post-transcriptional control

RNA processing, lifetime of mRNA, masked messengers, polypeptide cleaving, metabolic regulation

C. Development of genomically equivalent cells

  1. Determination - restriction of developmental potential involving regulatory or homeotic genes

  2. Differentiation - expression of different genes, resulting in specialized cells with characteristic proteins

D. Regulatory malfunction disease examples

  1. Triple repeat diseases
    a. Fragile X syndrome -form of mental retardation accompanied by large testicles and a characteristic long face, associated with fragile sites on the q end of the x chromosome. It may occur in a mild form, or be passed by, in females. The expansion of CGG, with more that 70 repeats is considered at risk. Normal individuals have 6 to 54 repeats. This mutation occurs before the structural gene and prevents the transcription of the protein.

    (> 70 repeats of CGG = risk)

    b. Myotonic Dystrophy - a disorder of nuclear wasting that increases in severity with each generation as the gene enlarges. The symptoms include progressive muscle weakness, cataracts and endocrine disturbances. The mechanisms of action for the triple repeat of CTG in an area after the structural gene is unknown. Normal individuals have 5 to 27 copies of the repeat, minimally affected have 50 copies, severely affected have thousands of triple CTG repeats.

    (1000's of repeats of CTG = severe disease.)

    c. Spinal Bulbar Muscle Atrophy (Kennedy's Disease) - adult onset neurological degeneration. The gene is located on the X chromosome. The triple repeats of CAG are found within the structural gene sequence, affected individuals have about 150 repeats, a small number, but greater than normal individuals. CAG repeats codes for polyglutamine and may prevent the normal androgen receptor gene from functioning properly in motor neurons.

    (> 150 repeats of CAG = risk)

    d. Huntington's Disease - another adult onset neurological disorder is also a triple CAG repeat. The neurological deterioration generally begins in the 40's. It is an autosomal dominant trait. The exact location and action of the poly-repeat is not known at this time.

  2. Cancer - defined as the loss of cell division control. It has been determined that it takes five to six mutations in one cell for cancer to occur. In the case of children fewer mutations are necessary. From 30 to 40 years of age those who develop cancer probably inherited a predisposition to cancer that allows the cells to develop cancerous conditions with fewer mutations. The most recent information indicates three types of mutation, all related to genomic control. Viruses cause less that 0.01% of cancers by gene insertion.

    a. Oncogenes - positive regulators (a switch turns on and stays on) that cause the acceleration of cell division

    b. Tumor suppressor genes - negative regulators (a switch is turned off) that cause the lack of function

    c. Mutator genes - cell normally corrects many errors that result from replication and protein synthesis. This mutation prevents self repair and increases the damage done by the oncogenes and suppressor mutations. DNA polymerase may be involved.

  3. Homeotic genes, homeoboxes, are believed to be 'master' regulatory genes that orchestrate the coordinated action of a number of genes, which, in turn, determine the development of a large region or body segment. These genes have been conserved, remained the same, in very different organisms. Homologous amino acid sequences are found in yeast, Drosophila, mouse and human.

References:

  1. Campbell, Neil, et al. 1993. Biology, 3d ed., The Benjamin Cummings Publishing Co.

  2. Micklos, David A. and Freyer, Greg, 1990. DNA Science, Cold Spring Harbor Press.

  3. Caskey, C. Thomas, M.D. April 21, 1993. "Molecular Medicine." JAMA. pp. 1986-91.

  4. Freedenberg, Debra M.D. June, 1994. "What Your Mother and Mendel Never Told You." Medical Grand Rounds, Scott and White Hospital. Temple, TX.

  5. Lewis, Ricki. 1994. Human Genetics Case Workbook. Brown Publishing.

  6. "Repeated to Death." January, 1994. Discover. p. 89-90

  7. Alberts, Bruce, et al. 1994 The Molecular Biology of the Cell. 3rd edition, Garland Publishing.


Materials And Teacher Procedure:

  1. Lego blocks of different sizes and colors attached to velcro strips allow models to be made and arranged in different confirmations on any surface for a teacher demonstration.

  2. A second option is magnetic strips cut to size, coded by the use of colored tape and arranged on a magnetic black board or small magnetic board.

  3. Laminated colored strips in student group packets would allow students to construct the models after a teacher demonstration.

  4. This could also be used for a performance assessment, remedial or tutorial reteaching.

Model Template Examples:

RNA processing shows the excising of introns and the selective arrangement of exons with Cap and poly A additions. The shaded areas should be contrasting colors. Color examples may be found in the referenced text.

Gene Amplification is a process in which the codons are duplicated. This may be an active, regulatory processor a passive, mutational process as seen in cancer and triplet repeat disease.

Model Template Suggestions: (see references for specific examples)

A. Review of prokaryotic cell control

  1. Transposons: movable elements that change expression

  2. Promoters; before, during and after the structural gene

  3. Operons; negative and positive controls
B. Eukaryotic control:

  1. Transcriptional control: Enhancer and promoter regions

  2. Post-transcriptional: RNA processing

  3. Developmental processes: Hemoglobin subunits, including embyro, pseudogenes and adult forms. Homeobox conservation in a variety of species.

  4. Disease processes: gene amplification examples including triplet repeats. All forms of cancer, including insertion and deletion mutations.


STUDENT WORKSHEET:
CONTROL OF GENE EXPRESSION

INSTRUCTIONS:

The control of expression of DNA into proteins may be divided into two main categories: transcriptional and post-transcriptional. Using the models provided and your teacher's instructions, construct examples of the following control mechanisms. As you construct the models, discuss disease processes that result from the malfunction of these control mechanisms and complete the following table.


Woodrow Wilson Index


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