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Chapter 18 Regulation of Gene Expression Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Overview: Conducting the Genetic Orchestra 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 Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-1 Figure 18.1 What regulates the precise pattern of expression of different genes? Concept 18.1: Bacteria often respond to environmental change by regulating transcription Natural selection has favored bacteria that produce only the products needed by that cell A cell can regulate the production of enzymes by feedback inhibition or by gene regulation Gene expression in bacteria is controlled by the operon model Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-2 Precursor Feedback inhibition trpE gene Figure 18.2 Regulation of a metabolic pathway Enzyme 1 trpD gene Regulation of gene expression Enzyme 2 trpC gene trpB gene Enzyme 3 trpA gene Tryptophan (a) Regulation of enzyme activity (b) Regulation of enzyme production Operons: The Basic Concept An operon is a cluster of genes whose protein product can be turned on or off depending upon the needs of the organism. 3 parts of the Operon: 1. 2. 3. Operator: controls access of RNA Pol to genes (near promoter) Promoter: where RNA Pol attaches Genes of the Operon: stretch of DNA required for enzymes made by the operon Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Regulatory Genes produce repressor proteins Repressors act like an ‘off’ switch by blocking RNA Pol and therefore transcription of genes • • Repressors are usually on, but can be inhibited 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 • Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings • • • 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 Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings 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 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 (gene off) and switches the lac operon off Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-4 Regulatory gene Promoter Operator lacZ lacI DNA No RNA made 3 mRNA RNA polymerase 5 Figure 18.4 The lac operon in E. coli: regulated synthesis of inducible enzymes Active repressor Protein (a) Lactose absent, repressor active, operon off lac operon DNA lacZ lacY -Galactosidase Permease lacI 3 mRNA 5 RNA polymerase mRNA 5 Protein Allolactose (inducer) lacA Inactive repressor (b) Lactose present, repressor inactive, operon on Transacetylase 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 the end product (higher levels) Regulation of the trp and lac operons involves negative control of genes because operons are switched off by the active form of the repressor Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Positive Gene Regulation Some operons are controlled through a stimulatory protein such as catabolite activator protein (CAP), an activator of transcription Ex. Low glucose in E. coli=CAP activation (through binding of cyclic AMP) Activated CAP attaches to the promoter of the lac operon and increases attraction of RNA polymerase= faster transcription High glucose levels=CAP detaches from the lac operon, and transcription slows Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-5 Promoter Operator DNA Figure 18.5 Positive control of the lac operon by catabolite activator protein (CAP) lacI lacZ RNA polymerase binds and transcribes CAP-binding site Active CAP cAMP Inactive lac repressor Inactive CAP Allolactose (a) Lactose present, glucose scarce (cAMP level high): abundant lac mRNA synthesized Promoter DNA lacI CAP-binding site Inactive CAP Operator lacZ RNA polymerase less likely to bind Inactive lac repressor (b) Lactose present, glucose present (cAMP level low): little lac mRNA synthesized Concept 18.2: Eukaryotic gene expression can be regulated at any stage All organisms must regulate which genes are expressed at any given time Differences between cell types result from differential gene expression: the expression of different genes by cells with the same genome Errors in gene expression can lead to diseases including cancer Gene expression is regulated at many stages Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-6 Signal NUCLEUS Chromatin Chromatin modification DNA Gene available for transcription Gene Transcription Figure 18.6 Stages in gene expression that can be regulated in eukaryotic cells RNA Exon Primary transcript Intron RNA processing Tail Cap mRNA in nucleus Transport to cytoplasm CYTOPLASM mRNA in cytoplasm Degradation of mRNA Translatio n Polypeptide Protein processing Active protein Degradation of protein Transport to cellular destination Cellular function Regulation of Chromatin Structure Genes within highly packed heterochromatin are usually not expressed Less accessible for transcription Chemical modifications to histones and DNA of chromatin influence both chromatin structure and gene expression 1. 2. 3. Histone acetylation Addition of methyl groups (methylation) Addition of phosphate groups (phosphorylation) Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Histone tails 1. Histone acetylation , acetyl groups are attached to positively charged lysines in histone tail a) DNA double helix Amino acids available for chemical modification loosens chromatin structure, promoting transcription (a) Histone tails protrude outward from a nucleosome Unacetylated histones Acetylated histones (b) Acetylation of histone tails promotes loose chromatin structure that permits transcription DNA Methylation (on DNA) Addition of methyl groups (methylation) condenses chromatin; inhibits transcription In genomic imprinting, methylation regulates expression of either the maternal or paternal alleles of certain genes at the start of development Addition of phosphate groups (phosphorylation) loosens chromatin, promoting transcription Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings 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 Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-8-3 Enhancer (distal control elements) Poly-A signal sequence Termination region Proximal control elements Exon Intron Exon Intron Exon DNA Upstream Downstream Promoter Primary RNA 5 transcript Transcription Exon Intron Exon Intron Exon RNA processing Cleaved 3 end of primary transcript Poly-A signal Intron RNA Coding segment mRNA 3 5 Cap 5 UTR Start codon Stop codon 3 UTR Poly-A tail Associated with most eukaryotic genes are control elements, segments of noncoding DNA that help regulate transcription by binding certain proteins Enhancers and Specific Transcription Factors To initiate transcription, eukaryotic RNA polymerase requires the assistance of proteins called 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 Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-9-3 Promoter Activators DNA Enhancer Distal control element TATA box General transcription factors Transcription initiation complex An activator is a protein that binds to an enhancer and stimulates transcription of a gene Gene DNA-bending protein Group of mediator proteins RNA polymerase II Bound activators cause mediator proteins to interact with proteins at the promoter RNA polymerase II Transcription initiation complex RNA synthesis Mechanisms of Post-Transcriptional Regulation Transcription alone does not account for gene expression Regulatory mechanisms can operate at various stages after transcription Such mechanisms allow a cell to fine-tune gene expression rapidly in response to environmental changes Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-11 alternative RNA splicing, different mRNA molecules are produced from the same primary transcript, (intron and exon segments are changed) Exons DNA Troponin T gene Primary RNA transcript RNA splicing mRNA or Initiation of Translation 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 Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-12 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 Ubiquitin Proteasome Protein to be degraded Ubiquitinated protein Proteasome and ubiquitin to be recycled Protein entering a proteasome Protein fragments (peptides) Concept 18.3: Noncoding RNAs play multiple roles in controlling gene expression 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: mRNA translation and chromatin configuration Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-13 Hairpin miRNA Hydrogen bond Dicer miRNA 5 3 (a) Primary miRNA transcript miRNAprotein complex MicroRNAs (miRNAs) are small single-stranded RNA molecules that can bind to mRNA These can degrade mRNA or block its translation mRNA degraded Translation blocked (b) Generation and function of miRNAs 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 Small RNAs may also block transcription of specific genes Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Concept 18.4: A program of differential gene expression leads to the different cell types in a multicellular organism 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 Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings A Genetic Program for Embryonic Development 1. 2. 3. The transformation from zygote to adult results from: Cell division: series of mitotic divisions (increase # of cells) Cell differentiation: process by which cells become specialized in structure and function Morphogenesis: physical processes that give an organism its shape (a) Fertilized eggs of a frog Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings (b) Newly hatched tadpole What controls differentiation and morphogenesis? 1. 2. 3. 4. Cytoplasmic determinants Cell-cell signals Determination Pattern formation Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-15 1. Cytoplasmic determinants are maternal substances in the egg that influence early development. These are distributed unevenly in the early cells of the embryo and results in different effects Unfertilized egg cell Sperm Fertilization Nucleus Two different cytoplasmic determinants Zygote Mitotic cell division Two-celled embryo (a) Cytoplasmic determinants in the egg Early embryo (32 cells) Signal transduction pathway Signal receptor Signal molecule (inducer) (b) Induction by nearby cells NUCLEUS 2. Cell-cell signals In the process called induction, signal molecules from embryonic cells cause transcriptional changes in nearby target cells and induce differentiation of specialized cell types Animation: Cell Signaling Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings 3. Determination commits a cell to its final fate After cell-cell signaling irreversible Cell differentiation is marked by the production of tissue-specific proteins Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings 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 Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings 4. 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 gradients of substances called morphogens establish an embryo’s axes and other features Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-17 Head Thorax Abdomen 0.5 mm Dorsal In Drosophila, cytoplasmic determinants in the unfertilized egg determine the axes before fertilization BODY Anterior AXES Left Right Posterior Ventral (a) Adult Follicle cell 1 Egg cell developing within ovarian follicle Egg cell Nurse cell Egg shell 2 Unfertilized egg After fertilization, the embryo develops into a segmented larva with three larval stages Nucleus Depleted nurse cells Fertilization Laying of egg 3 Fertilized egg Embryonic development 4 Segmented embryo 0.1 mm Body segments Hatching 5 Larval stage (b) Development from egg to larva Fig. 18-19 EXPERIMENT Tail Head 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 T1 T2 T3 A1 A2 A6 A3 A4 A5 A8 A7 Wild-type larva Tail Tail A8 A8 A7 A6 A7 Mutant larva (bicoid) RESULTS 100 µm Bicoid mRNA in mature unfertilized egg Fertilization, translation Anterior end of bicoid Bicoid protein in early mRNA embryo CONCLUSION Nurse cells Egg bicoid mRNA Developing egg Bicoid mRNA in mature unfertilized egg Bicoid protein in early embryo Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings