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AP Biology 12 Regulation of Prokaryote and Eukaryote Genomes (Chapter 18) How does this all fit together??? Big Idea 2: Biological systems utilize free energy and molecular building blocks to grow, to reproduce and to maintain dynamic homeostasis. Essential knowledge Chapters/sections 2.e.1 Timing and coordination of specific events are necessary for the normal development of an organism, and these events are regulated by a variety of mechanisms. 18.2, 18.3, 18.4 38.1 Illustrative examples covered • Morphogenesis of fingers and toes • Immune function • C. elegans development • Flower Development Big Idea 3: Living systems store, retrieve, transmit and respond to information essential to life processes. 3.B.1 Gene 18.1, 18.2, 18.3 • Promoters regulation results in • Terminators differential gene • Enhancers expression, leading to cell specialization. 3.B.2 A variety of intercellular and intracellular signal transmissions mediate gene expression. 11.1, 11.4 18.1, 18.2, 18.3, 18.4 • Cytokines regulate gene expression to allow for cell replication and division • Mating pheromones in yeast trigger mating gene expression • Levels of cAMP regulate metabolic gene expression in bacteria • Expression of the SRY gene triggers the male sexual development pathway in animals • Ethylene levels cause changes in the production of different enzymes, allowing fruits to ripen • Seed germination and gibberellin • Mating pheromones in yeast trigger mating genes expression and sexual reproduction • Morphogens stimulate cell differentiation and development • Changes in p53 activity can result in cancer • HOX genes and their role in development Big Idea 4: Biological systems interact, and these systems and their interactions possess complex properties. 4.A.3: Interactions between external stimuli and regulated gene expression result in specialization of cells, tissues and organs. 18.4 No illustrative examples listed in the Curriculum Framework. Cell Processes and Applications – Gene Regulation (Chapter 18) Describe similarities and differences between prokaryotic and eukaryotic genomes Describe some mechanisms by which gene expression is regulated in prokaryotes and eukaryotes Describe cancer with respect to: abnormal nuclei disorganized and uncontrolled growth (anaplasia) lack of contact inhibition vascularization metastasis List the seven danger signals that may indicate the presence of cancer (handout/notes) Differentiate between a proto-oncogene and an oncogene Use examples to outline the roles of initiators and promoters in carcinogenesis (handouts/notes) Demonstrate a knowledge of how a virus can bring about carcinogenesis Overview: Conducting the Genetic Orchestra Both prokaryotes and eukaryotes alter their patterns of gene expression in response to changes in environmental conditions. In multicellular eukaryotes, each cell type contains the same genome but expresses a different subset of genes. During development, gene expression must be carefully regulated to ensure that the right genes are expressed only at the correct time and in the correct place. Gene expression in eukaryotes and bacteria is often regulated at the transcription stage. ○ Control of other levels of gene expression is also important. RNA molecules play many roles in regulating eukaryotic gene expressions. Disruptions in gene regulation can lead to cancer. MP3 Tutor: Control of Gene Expression chapter 18 website D8: Describe some mechanisms by which gene expression is regulated in prokaryotes (and eukaryotes.) How do prokaryotes control their metabolic pathways? For example, how do they control the metabolic pathway that synthesizes the amino acid tryptophan? Natural selection favors bacteria that express only those genes whose products are needed by the cell. ○ A bacterium in a tryptophan-rich environment that stops producing tryptophan conserves its resources. Metabolic control occurs on two levels. First, cells can adjust the activity of enzymes already present. ○ This may happen by feedback inhibition, in which the activity of the first enzyme in a pathway is inhibited by the pathway’s end product. ○ Feedback inhibition, typical of anabolic (biosynthetic) pathways, allows a cell to adapt to short-term fluctuations in the supply of a needed substance. Second, cells can vary the number of specific enzyme molecules they make by regulating gene expression. ○ Genes of the bacterial genome may be switched on or off by changes in the metabolic status of the cell. Describe how bacteria use a repressible operon to ‘turn the tap’ on and off a metabolic pathway that is producing a molecule that the cell requires – for example, tryptophan. http://bcs.whfreeman.com/thelifewire/content/chp13/1302002.html • • • 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. That means that the oerator controls transcription. 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 Repressible and Inducible Operons: Two Types of Negative Gene Regulation • • • A repressible operon is one that is usually on; binding of a repressor to the operator shuts off transcription The trp operon is a repressible operon An inducible operon is one that is usually off; a molecule called an inducer inactivates the repressor and turns on transcription Describe how bacteria use inducible operons to turn on metabolic pathways when a particular metabolite is present. (See Activity: The lac Operon in E. coli) • The lac operon is an inducible operon and contains genes that code for enzymes used in the hydrolysis and metabolism of lactose • By itself, the lac repressor is active and switches the lac operon off • A molecule called an inducer inactivates the repressor to turn the lac operon on • • 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 Describe how bacteria ‘fine tune’ the control of the lac operon, depending on whether glucose is present or absent – positive gene regulation See Lac operon animations: http://www.dartmouth.edu/~cbbc/courses/movies/LacOperon.html does not work on chrome • • • • • Some operons are also subject to positive control through a stimulatory protein, such as catabolite activator protein (CAP), an activator of transcription When glucose (a preferred food source of E. coli) is scarce, CAP is activated by binding with cyclic AMP Activated CAP attaches to the promoter of the lac operon and increases the affinity of RNA polymerase, thus accelerating transcription When glucose levels increase, CAP detaches from the lac operon, and transcription returns to a normal rate CAP helps regulate other operons that encode enzymes used in catabolic pathways The Regulation of Eukaryotic Gene Expression Ref:18.2 Here is a photo of a salamander egg (a eukaryotic cell) in interphase. You can see that some parts are ‘unwound’ as the genes in this region are being expressed: A major concept in cell differentiation in multicellular eukaryotes is ‘differential gene expression’. What is meant by this? • In multicellular organisms gene expression is essential for cell specialization • To perform it’s role each gene must maintain a specific program of gene expression in which certain genes are expressed and others are not. • A human cell expresses about 20% of it’s genes at any one time. The more highly differentiated the cells are the smaller the fraction of genes expressed. D8: Describe some mechanisms by which gene expression is regulated in (prokaryotes and) eukaryotes. (Cell differentiation involves differential gene expression) 18_PPTLecture\1621DNAPacking_A.swf Note: only about 20% of the genome of a typical human cell is being expressed at any one time. In a human, only about 1.5% of the DNA codes for protein. Eukaryotic Control of Gene Expression (see web activity in chapter 18) __also page 356 The DNA of eukaryotic cells is packaged with proteins in a complex called chromatin. Genes within highly packed heterochromatin are usually not expressed presumably because transcription proteins cannot reach the DNA. Chemical modifications of the histones and DNA of chromatin play a key role in chromatin structure and gene expression. The N-terminus of each histone molecule in a nucleosome protrudes outward from the nucleosome. ○ These histone tails are accessible to various modifying enzymes, which catalyze the addition or removal of specific chemical groups. Histone acetylation (addition of an acetyl group, —COCH3) and deacetylation appear to play a direct role in the regulation of gene transcription. Acetylated histones grip neighboring nucleosomes less tightly, providing easier access for transcription proteins in this region. Several other chemical groups, such as methyl and phosphate groups, can be reversibly attached to amino acids in histone tails. ○ The attachment of methyl groups (—CH3) to histone tails leads to condensation of chromatin. DNA methylation reduces gene expression. ○ The addition of a phosphate group (phosphorylation) to an amino acid next to a methylated amino acid has the opposite effect. This diagram is from chapter 16 and it shows how the DNA in eukaryotes is packed using various histone proteins. The corresponding electron micrographs of the DNA at the various stages is also shown. Some interesting facts about the human genome: The total number of genes in the human genome is about 25,000. Each chromosome has about 1.5 X 108 nucleotide pairs (average) and is about 4 cm long if stretched out. The total DNA from both parents is about 2 meters per cell if stretched out. How does it fit into the cell, along with the other 45 chromosomes? What is the difference between heterochromatin and euchromatin? Euchromatin is the less condensed form of eukaryotic chromatin that is available for transcription. Heterochromatin is eukaryotic chromatin that remains highly compacted during interphase and is generally not transcribed. In what form is the chromatin during interphase? ______________________________________________________________________________ ______________________________________________________________________________ • • 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 a) Regulation of Chromatin Structure - Control of DNA packing and unpacking: How are ‘methylation’ and ‘acetylation’ involved in the packing and unpacking of chromatin? Histone acetylation (addition of an acetyl group, —COCH3) and deacetylation appear to play a direct role in the regulation of gene transcription. Acetylated histones grip neighboring nucleosomes less tightly, providing easier access for transcription proteins in this region. ○ Some of the enzymes responsible for acetylation or deacetylation are associated with or are components of transcription factors that bind to promoters. Thus, histone acetylation enzymes may promote the initiation of transcription not only by modifying chromatin structure but also by binding to and recruiting components of the transcription machinery. Several other chemical groups, such as methyl and phosphate groups, can be reversibly attached to amino acids in histone tails. ○ The attachment of methyl groups (—CH3) to histone tails leads to condensation of chromatin. ○ The addition of a phosphate group (phosphorylation) to an amino acid next to a methylated amino acid has the opposite effect. How does the eukaryote cell control the transcription of specific genes? Activity: Control of Transcription The control of transcription in eukaryotes depends on the binding of activators to DNA control elements. Explain why liver cells transcribe the albumin gene (a blood protein) and not the crystalline gene (main protein of the lens), whereas lens cells express the crystalline gene and not the albumin gene. Refer to fig. 18.1 page 361 The specific transcription factors. All activators required for high level expression of the albumin gene are only present in liver cells and high level expression of the crystalline gene are only present in lens cells _______________________________________ Multiple control elements are associated with most eukaryotic genes. ○ Control elements are noncoding DNA segments that regulate transcription by binding certain proteins. ○ These control elements and the proteins they bind are critical to the precise regulation of gene expression in different cell types. _______________________________________ _______________________________________ _______________________________________ __________________________________ Activators can bind to enhancers and influence the promoter region of a gene thousands of nucleotides away. Several protein transcription factors must be present in order for RNA polymerase to transcribe the gene: ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ How does the eukaryotic cell turn on all the genes needed for a particular metabolic pathway at the same time? (co-ordinately controlled genes) Control elements for the various genes are all activated together, even though the genes are widely spaced throughout the genome. ○ Coordinate gene expression in eukaryotes depends on the association of a specific control element or combination of control elements with every gene of a dispersed group. ○ A common group of transcription factors binds to all the genes in the group, promoting simultaneous gene transcription. For example, a steroid hormone enters a cell and binds to a specific receptor protein in the cytoplasm or nucleus, forming a hormone–receptor complex that serves as a transcription activator. ○ Other signal molecules control gene expression indirectly by triggering signal-transduction pathways that lead to activation of transcription. ○ Every gene whose transcription is stimulated by that steroid hormone has a control element recognized by that hormone–receptor complex. The principle of coordinate regulation is the same: Genes with the same control elements are activated by the same chemical signals. Systems for coordinating gene regulation probably arose early in evolutionary history and evolved by the duplication and distribution of control elements within the genome. A Eukaryotic Gene and Its Transcript ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ Post-transcriptional control of gene expression may involve alternative methods of RNA processing: Activity on Mastering Biology: Post transcriptional control mechanisms RNA Processing page 362 READ Alternative RNA splicing. Page 363 Figure 18.13 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. ○ Regulatory proteins specific to a cell type control intron-exon choices by binding to regulatory sequences within the primary transcript. ○ Alternative RNA splicing significantly expands the repertoire of a set of genes. The life span of an mRNA molecule is an important factor in determining the pattern of protein synthesis. Animation mRNA degradation on hard drive Prokaryotic mRNA molecules are typically degraded after only a few minutes. Eukaryotic mRNAs typically last for hours, days, or weeks. ○ In red blood cells, mRNAs for hemoglobin polypeptides are unusually stable and are translated repeatedly. Post-transcriptional control may involve passage of the mRNA molecule through the nuclear envelope , mRNA degradation, control of translation of the mRNA, protein modification, or protein degradation by a proteasome: Animation: Blocking Translation (on hard drive) Refer to Fig 18.15 page 365 This diagram shows how translation of an mRNA molecule can be blocked by the presence of another type of RNA (miRNA) microRNAs: This is a type of translational control. As well, it shows how mRNA can be degraded, which is another type of post-translational control of gene expression. SiRNA, small interfering RNAs, have the same effect. Animation: Protein Processing – hard drive Animation: Protein Degradation hard drive Cell Differentiation in Multicellular Organisms What are some of the factors within the cell that lead to differential gene expression and ultimately cell specialization in multicellular organisms? Cytoplasmic materials are distributed unevenly in the unfertilized egg ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ Animation: Cell Signaling In cell specialization, determination is followed by differentiation: Muscle cells develop from embryonic precursors that have the potential to develop into a number of alternative cell types, including cartilage cells, fat cells, or multinucleate muscle cells. ○ Particular conditions commit certain embryonic precursors to become muscle cells. ○ Although the committed cells are unchanged, they are now myoblasts. ○ Eventually, the myoblasts begin to synthesize muscle-specific proteins and fuse to form mature, elongated, multinucleate skeletal muscle cells. ○ Researchers isolated different genes by causing each to be expressed in a separate embryonic precursor cell and then looking for differentiation into myoblasts and muscle cells. ○ They identified several “master regulatory genes” that, when transcribed and translated, commit the cells to become skeletal muscle. One of these master regulatory genes is called myoD. myoD encodes MyoD protein, a transcription factor that binds to specific control elements in the enhancers of various target genes and stimulates their expression. Some target genes for MyoD encode for other muscle-specific transcription factors. MyoD also stimulates expression of the myoD gene itself, perpetuating its effect in maintaining the cell’s differentiated state. This diagram illustrates some of the stages in the development of the Drosophila larva, an organism that has been highly studied: (on evolution video Great transformations) Scientists studied mutations in Drosophila in order to understand the molecular basis of pattern formation, which is the development of a spatial organization in which the tissues and organs are in their characteristic places. Early studies of this type were carried out by Edward Lewis. He discovered the homeotic genes. Much further work on developmental genes was carried out by Nǖsslein-Volhard and Wieschaus about 30 years later. Many of their experiments involved maternal effect genes (also called egg polarity genes) that are responsible for setting up the cytoplasmic determinants in the egg. Here is one example experiment: 18.5 Cancer results from genetic changes that affect the cell cycle: (not for exam) What is a proto-oncogene? ______________________________________________________________________________ ______________________________________________________________________________ Identify 3 ways that a proto-oncogene can be modified and thereby lead to cancer: Page 374 ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ __________________________________________________________ Oncogene proteins and faulty tumor-suppressor proteins interfere with normal signalling pathways: Multiple mutations underlie the development of cancer (carcinogenesis):