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Regulation of Gene Expression
Chapter 18 Regulation of Gene Expression
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activity production Feedback inhibition Regulation of gene expression
Precursor Feedback inhibition trpE gene Enzyme 1 trpD gene Regulation of gene expression Enzyme 2 trpC gene trpB gene Figure 18.2 Regulation of a metabolic pathway Enzyme 3 trpA gene Tryptophan (a) Regulation of enzyme activity (b) Regulation of enzyme production
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Polypeptide subunits that make up enzymes for tryptophan synthesis
trp Operon - Repressible trp operon Promoter Promoter Genes of operon DNA trpR trpE trpD trpC trpB trpA Regulatory gene Operator Start codon Stop codon 3 mRNA 5 mRNA RNA polymerase 5 E D C B A Protein Inactive repressor Polypeptide subunits that make up enzymes for tryptophan synthesis (a) Tryptophan absent, repressor inactive, operon on. DNA No RNA made Figure 18.3 The trp operon in E. coli: regulated synthesis of repressible enzymes mRNA Protein Active repressor Tryptophan (corepressor) (b) Tryptophan present, repressor active, operon off.
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Allolactose inducer lac Operon - inducible Regulatory gene Promoter
Operator DNA lacI lacZ No RNA made 3 mRNA RNA polymerase 5 Active repressor Protein (a) Lactose absent, repressor active, operon off. lac operon DNA lacI lacZ lacY lacA RNA polymerase Figure 18.4 The lac operon in E. coli: regulated synthesis of inducible enzymes For the Cell Biology Video Cartoon Rendering of the lac Repressor from E. coli, go to Animation and Video Files. 3 mRNA mRNA 5 5 -Galactosidase Permease Protein Transacetylase Allolactose inducer Inactive repressor (b) Lactose present, repressor inactive, operon on.
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Positive Gene Regulation
Promoter Operator DNA lacI lacZ CAP-binding site RNA polymerase binds and transcribes Active CAP cAMP Inactive lac repressor Inactive CAP Allolactose (a) Lactose present, glucose scarce (cAMP level high): abundant lac mRNA synthesized Promoter Operator DNA lacI lacZ Figure 18.5 Positive control of the lac operon by catabolite activator protein (CAP) CAP-binding site RNA polymerase less likely to bind Inactive CAP Inactive lac repressor (b) Lactose present, glucose present (cAMP level low): little lac mRNA synthesized
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Histone Modifications Acetylation Promotes Transcription
tails Amino acids available for chemical modification DNA double helix (a) Histone tails protrude outward from a nucleosome. Figure 18.7 A simple model of histone tails and the effect of histone acetylation Unacetylated histones Acetylated histones (b) Acetylation of histone tails promotes loose chromatin structure that permits transcription.
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distal control elements
Control Elements = Transcription Factors Poly-A signal sequence Enhancer distal control elements Proximal control elements Termination region Exon Intron Exon Intron Exon DNA Upstream Downstream Promoter Transcription Primary RNA transcript Exon Intron Exon Intron Exon Cleaved 3 end of primary transcript 5 RNA processing Intron RNA Poly-A signal Figure 18.8 A eukaryotic gene and its transcript Coding segment mRNA 3 Start codon Stop codon 5 Cap 5 UTR 3 UTR Poly-A tail
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Activators Enhancer General transcription factors Transcription
Promoter Gene DNA Distal control element Enhancer TATA box General transcription factors DNA-bending protein Group of mediator proteins RNA polymerase II Figure 18.9 A model for the action of enhancers and transcription activators RNA polymerase II Transcription initiation complex RNA synthesis
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Alternative RNA Processing
Exons DNA Troponin T gene Primary RNA transcript Figure Alternative RNA splicing of the troponin T gene RNA splicing mRNA or
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Proteasome - Protein Degradation
and ubiquitin to be recycled Ubiquitin Proteasome Protein to be degraded Ubiquitinated protein Protein fragments (peptides) Protein entering a proteasome Figure Degradation of a protein by a proteasome
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Modifiers of Translation
Hairpin miRNA Hydrogen bond Dicer miRNA miRNA- protein complex 5 3 (a) Primary miRNA transcript Figure Regulation of gene expression by miRNAs mRNA degraded Translation blocked (b) Generation and function of miRNAs
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(a) Fertilized eggs of a frog (b) Newly hatched tadpole
Fig Figure From fertilized egg to animal: What a difference four days makes (a) Fertilized eggs of a frog (b) Newly hatched tadpole
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Differential Gene Expression
Unfertilized egg cell Sperm Nucleus Fertilization Two different cytoplasmic determinants NUCLEUS Early embryo (32 cells) Zygote Signal transduction pathway Mitotic cell division Signal receptor Figure Sources of developmental information for the early embryo Two-celled embryo Signal molecule (inducer) (a) Cytoplasmic determinants in the egg (b) Induction Signals by nearby cells
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MyoD Protein - Muscle Cell Differentiation
Nucleus Master regulatory gene myoD Other muscle-specific genes DNA Embryonic precursor cell OFF OFF mRNA OFF MyoD protein (transcription factor) Myoblast (determined) Figure Determination and differentiation of muscle cells mRNA mRNA mRNA mRNA Myosin, other muscle proteins, and cell cycle– blocking proteins MyoD Another transcription factor Part of a muscle fiber (fully differentiated cell)
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BODY AXES Pattern Formation in Drosophila fruit fly
Head Thorax Abdomen 0.5 mm BODY AXES Dorsal Right Anterior Posterior Left Ventral (a) Adult Follicle cell 1 Egg cell developing within ovarian follicle Nucleus Egg cell Nurse cell 2 Unfertilized egg Egg shell Depleted nurse cells Fertilization Laying of egg 3 Fertilized egg Figure Key developmental events in the life cycle of Drosophila Embryonic development 4 Segmented embryo 0.1 mm Body segments Hatching 5 Larval stage (b) Development from egg to larva
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Affects Polarity Development
Bicoid Protein Affects Polarity Development EXPERIMENT Tail Head T1 T2 A8 T3 A7 A1 A2 A6 A3 A4 A5 Wild-type larva Tail Tail A8 A8 A7 A6 A7 Mutant larva (bicoid) RESULTS Figure Is Bicoid a morphogen that determines the anterior end of a fruit fly? Fertilization, translation of bicoid mRNA 100 µm Anterior end Bicoid mRNA in mature unfertilized egg Bicoid protein in early embryo CONCLUSION Nurse cells Egg bicoid mRNA Developing egg Bicoid mRNA in mature unfertilized egg Bicoid protein in early embryo
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within a control element within the gene
Proto-oncogene to Oncogene Proto-oncogene DNA Translocation or transposition: Gene amplification: Point mutation: within a control element within the gene New promoter Oncogene Oncogene Figure Genetic changes that can turn proto-oncogenes into oncogenes Normal growth- stimulating protein in excess Normal growth-stimulating protein in excess Normal growth- stimulating protein in excess Hyperactive or degradation- resistant protein
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EFFECTS OF MUTATIONS Multi-Step Model of Cancer Development
Colon EFFECTS OF MUTATIONS Loss of tumor- suppressor gene APC (or other) 1 Activation of ras oncogene 2 Loss of tumor-suppressor gene p53 4 Colon wall Loss of tumor-suppressor gene DCC 3 Additional mutations 5 Figure A multistep model for the development of colorectal cancer Normal colon epithelial cells Small benign growth (polyp) Larger benign growth (adenoma) Malignant tumor (carcinoma)
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Genes not expressed Genes expressed Promoter Operator Genes
Review Genes not expressed Genes expressed Promoter Operator Genes Fig. 18-UN2 Active repressor: no inducer present Inactive repressor: inducer bound Fig. 18-UN3
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Eukaryotic Differential Gene Expression
Signal NUCLEUS Chromatin Chromatin modification DNA Gene available for transcription Gene Transcription RNA Exon Primary transcript Intron RNA processing Tail Cap mRNA in nucleus Transport to cytoplasm CYTOPLASM mRNA in cytoplasm Degradation of mRNA Translation Figure 18.6 Stages in gene expression that can be regulated in eukaryotic cells Polypeptide Protein processing Active protein Degradation of protein Transport to cellular destination Cellular function
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Protein processing and degradation
Regulation of Gene Expression Chromatin modification Transcription • Genes in highly compacted chromatin are generally not transcribed. • Regulation of transcription initiation: DNA control elements bind specific transcription factors. • Histone acetylation seems to loosen chromatin structure, enhancing transcription. Bending of the DNA enables activators to contact proteins at the promoter, initiating transcription. • DNA methylation generally reduces transcription. • Coordinate regulation: Enhancer for liver-specific genes Enhancer for lens-specific genes Chromatin modification Transcription RNA processing • Alternative RNA splicing: RNA processing Primary RNA transcript mRNA degradation Translation mRNA or Fig. 18-UN4 Protein processing and degradation Translation • Initiation of translation can be controlled via regulation of initiation factors. mRNA degradation • Each mRNA has a characteristic life span, determined in part by sequences in the 5 and 3 UTRs. Protein processing and degradation • Protein processing and degradation by proteasomes are subject to regulation.
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You should now be able to:
Explain the concept of an operon and the function of the operator, repressor, and corepressor. Explain the adaptive advantage of grouping bacterial genes into an operon. Explain how repressible and inducible operons differ and how those differences reflect differences in the pathways they control.
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Explain how DNA methylation and histone acetylation affect chromatin structure and the regulation of transcription. Define control elements and explain how they influence transcription. Explain the role of promoters, enhancers, activators, and repressors in transcription control.
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7. Explain how maternal effect genes affect polarity and development in Drosophila embryos.
8. Explain how mutations in tumor-suppressor genes can contribute to cancer.
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