* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download video slide
Gene nomenclature wikipedia , lookup
Genetic engineering wikipedia , lookup
RNA interference wikipedia , lookup
No-SCAR (Scarless Cas9 Assisted Recombineering) Genome Editing wikipedia , lookup
Genome evolution wikipedia , lookup
Epigenetics in learning and memory wikipedia , lookup
RNA silencing wikipedia , lookup
Non-coding DNA wikipedia , lookup
Epigenetics of neurodegenerative diseases wikipedia , lookup
Epigenetics of diabetes Type 2 wikipedia , lookup
Cancer epigenetics wikipedia , lookup
Genome (book) wikipedia , lookup
Oncogenomics wikipedia , lookup
Long non-coding RNA wikipedia , lookup
Epigenetics in stem-cell differentiation wikipedia , lookup
Gene therapy of the human retina wikipedia , lookup
History of genetic engineering wikipedia , lookup
Non-coding RNA wikipedia , lookup
Epitranscriptome wikipedia , lookup
Gene expression profiling wikipedia , lookup
Microevolution wikipedia , lookup
Nutriepigenomics wikipedia , lookup
Site-specific recombinase technology wikipedia , lookup
Polycomb Group Proteins and Cancer wikipedia , lookup
Designer baby wikipedia , lookup
Point mutation wikipedia , lookup
Epigenetics of human development wikipedia , lookup
Mir-92 microRNA precursor family wikipedia , lookup
Vectors in gene therapy wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Primary transcript wikipedia , lookup
Chapter 18 Regulation of Gene Expression PowerPoint® Lecture Presentations for Biology Eighth Edition Neil Campbell and Jane Reece Lectures by Chris Romero, updated by Erin Barley with contributions from Joan Sharp 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 Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings 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 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 • Operator -the regulatory “switch”, a segment of DNA – usually positioned within the promoter • Operon – (DNA) includes the operator, the promoter, and the genes that they control • In coordinate control, a cluster of functionally related genes can be controlled by a single onoff “switch” Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings • Repressor – (protein) switches the operon off – Prevents transcription by binding to the operator and blocking RNA polymerase – the product of a separate regulatory gene – can be in an active or inactive form, depending on the presence of other molecules – Corepressor – cooperates with a repressor protein to switch an operon off Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings • Function of the operator – when a repressor is bound to the operator, RNA poly cannot bind the promoter and transcription is turned “off” – when the repressor is not bound to the operator, RNA poly can bind the promoter and transcription is turned “on”. Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings • Ex: 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 Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-3a trp operon Promoter Promoter Genes of operon DNA trpR Regulatory gene mRNA 5 Protein trpE 3 Operator Start codon mRNA 5 RNA polymerase Inactive repressor E trpD trpC trpB trpA B A Stop codon D C Polypeptide subunits that make up enzymes for tryptophan synthesis (a) Tryptophan absent, repressor inactive, operon on Fig. 18-3b-2 DNA No RNA made mRNA Active repressor Protein Tryptophan (corepressor) (b) Tryptophan present, repressor active, operon off Repressible and Inducible Operons: Two Types of Negative Gene Regulation • Repressible operon - usually on – binding of a repressor shuts off transcription – Ex: trp operon • Inducible operon - usually off – an inducer inactivates the repressor and turns on transcription – Ex: lac operon Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-4a Regulatory gene Promoter Operator lacI DNA lacZ No RNA made 3 mRNA 5 Protein RNA polymerase Active repressor (a) Lactose absent, repressor active, operon off Fig. 18-4b 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 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 Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Positive Gene Regulation • Activator – (protein) when stimulated, changes shape and binds to the promoter – increasing the affinity of RNA polymerase to the promoter (increasing the rate of transcription). - stimulated by a small organic molecule such as cAMP. Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings – Ex: catabolite activator protein (CAP) – When glucose (a preferred food source of E. coli) is scarce, CAP is activated by binding with cAMP, it attaches to the promoter of the lac operon and increases the affinity of RNA polymerase, accelerating transcription. When glucose levels increase, CAP detaches and transcription returns to a normal rate Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-5 Promoter Operator DNA 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 – essential for cell specialization – All cells have the same genome but express different genes • 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 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 Differential Gene Expression • Differential gene expression, the expression of different genes by cells with the same genome skin cells and stomach cells both have the genes for making oils as well as HCl. Genes for oil are only expressed in skin cells and the genes for HCl are only expressed in stomach cells. Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Regulation of Chromatin Structure • Genes within highly packed heterochromatin are usually not expressed • Chemical modifications to histones and DNA of chromatin influence both chromatin structure and gene expression Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Histone Modifications • Histone acetylation - acetyl groups are attached to positively charged lysines in histone tails – When histones are acetylated, they lose their affinity to neighboring nucleosomes, this loosens the structure of the chromatin and provides the transcription proteins easier access to genes. Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-7 Histone tails DNA double helix Amino acids available for chemical modification (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 • DNA methylation - addition of methyl groups to certain bases in DNA reduces transcription – can cause long-term inactivation of genes in cellular differentiation • Ex: Genomic imprinting - methylation regulates expression of either the maternal or paternal alleles of certain genes during development Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Epigenetic Inheritance • 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 Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Organization of a Typical Eukaryotic Gene • Control elements - segments of noncoding DNA that help regulate transcription by binding certain 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 • Enhancer - section of the gene that binds together with activators and proteins including transcription factors for the transcription initiation complex on the promoter (this is part of coordinate control). Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-9-3 Promoter Activators DNA Enhancer Distal control element Gene TATA box General transcription factors DNA-bending protein Group of mediator proteins RNA polymerase II RNA polymerase II Transcription initiation complex RNA synthesis Fig. 18-10 Enhancer Promoter Control elements Albumin gene Crystallin gene LIVER CELL NUCLEUS Available activators LENS CELL NUCLEUS Available activators Albumin gene not expressed Albumin gene expressed Crystallin gene not expressed (a) Liver cell Crystallin gene expressed (b) Lens cell RNA Processing • Alternative RNA splicing can produce different mRNA molecules from the same primary transcript (regulatory proteins control which sections are treated as introns and exons) thus, more than one polypeptide can be produced from the a single gene. Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-11 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 • Proteasomes are giant protein complexes that bind protein molecules and degrade them Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings 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 Effects on mRNAs by MicroRNAs and Small Interfering RNAs • MicroRNAs (miRNAs) are small singlestranded RNA molecules that can bind to mRNA • RNA interference (RNAi) - inhibition of gene expression by RNA molecules – caused by small interfering RNAs (siRNAs) 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 mRNA degraded miRNAprotein complex Translation blocked (b) Generation and function of miRNAs Small RNAs • siRNAs and miRNAs are similar but form from different RNA precursors • miRNAs can degrade mRNA or block its translation • siRNAs play a role in heterochromatin formation and can block large regions of the chromosome • 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 • Cell differentiation - process by which cells become specialized in structure and function • Morphogenesis - the physical processes that give an organism its shape • Differential gene expression results from genes being regulated differently in each cell type Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Cytoplasmic Determinants and Inductive Signals • An egg’s cytoplasm contains RNA, proteins, and other substances that are distributed unevenly in the unfertilized egg • Cytoplasmic determinants - maternal substances in the egg that influence early development • As the zygote divides by mitosis, cells contain different cytoplasmic determinants, which lead to different gene expression Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-15 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 • Environmental factors - cell signaling • Induction - signal molecules from embryonic cells cause transcriptional changes in nearby target cells – interactions between cells induce differentiation of specialized cell types Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Determination and Differentiation • Determination commits a cell to its final fate – distribution of materials in the egg cell and cell signaling “tell” the cells what they will become – precedes differentiation Differentiation is the outcome of determination – 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 Fig. 18-16-3 Nucleus Master regulatory gene myoD Embryonic precursor cell Other muscle-specific genes DNA Myoblast (determined) OFF OFF mRNA OFF MyoD protein (transcription factor) mRNA MyoD Part of a muscle fiber (fully differentiated cell) mRNA Another transcription factor mRNA mRNA Myosin, other muscle proteins, and cell cycle– blocking proteins Drosophila – More Later! Head Thorax Abdomen 0.5 mm Dorsal BODY AXES Anterior Left Ventral (a) Adult Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Right Posterior Fig. 18-17b Follicle cell 1 Egg cell Nucleus developing within ovarian follicle Egg cell Nurse cell Egg shell 2 Unfertilized egg 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. 18-18 Eye Leg Antenna Wild type Mutant Concept 18.5: Cancer results from genetic changes that affect cell cycle control • The gene regulation systems that go wrong during cancer are the very same systems involved in embryonic development • Cancer can be caused by mutations to genes that regulate cell growth and division • Tumor viruses can cause cancer in animals including humans Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Oncogenes and Proto-Oncogenes • Oncogenes are cancer-causing genes • Proto-oncogenes are the corresponding normal cellular genes that are responsible for normal cell growth and division • Conversion of a proto-oncogene to an oncogene can lead to abnormal stimulation of the cell cycle Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-20 Proto-oncogene DNA Translocation or transposition: Point mutation: Gene amplification: within a control element New promoter Normal growthstimulating protein in excess Oncogene Normal growth-stimulating protein in excess Normal growthstimulating protein in excess within the gene Oncogene Hyperactive or degradationresistant protein • Proto-oncogenes can be converted to oncogenes by – Movement of DNA within the genome: if it ends up near an active promoter, transcription may increase – Amplification of a proto-oncogene: increases the number of copies of the gene – Point mutations in the proto-oncogene or its control elements: causes an increase in gene expression Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Tumor-Suppressor Genes • Tumor-suppressor genes help prevent uncontrolled cell growth – Repair damaged DNA – Control cell adhesion – Inhibit the cell cycle in the cell-signaling pathway • Mutations that decrease protein products of tumor-suppressor genes may contribute to cancer onset Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Interference with Normal Cell-Signaling Pathways • Mutations in the ras proto-oncogene and p53 tumor-suppressor gene are common in human cancers • Mutations in the ras gene can lead to production of a hyperactive Ras protein and increased cell division Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-21a 1 Growth factor 1 MUTATION Hyperactive Ras protein (product of oncogene) issues signals on its own Ras 3 G protein GTP Ras GTP 2 Receptor 4 Protein kinases (phosphorylation cascade) NUCLEUS 5 Transcription factor (activator) DNA Gene expression Protein that stimulates the cell cycle (a) Cell cycle–stimulating pathway • Suppression of the cell cycle can be important in the case of damage to a cell’s DNA; p53 prevents a cell from passing on mutations due to DNA damage • Mutations in the p53 gene prevent suppression of the cell cycle • Mutations in tumor-suppressor genes result in unchecked cell division Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-21b 2 Protein kinases MUTATION 3 Active form of p53 UV light 1 DNA damage in genome DNA Protein that inhibits the cell cycle (b) Cell cycle–inhibiting pathway Defective or missing transcription factor, such as p53, cannot activate transcription The Multistep Model of Cancer Development • Multiple mutations are generally needed for full-fledged cancer; thus the incidence increases with age • At the DNA level, a cancerous cell is usually characterized by at least one active oncogene and the mutation of several tumor-suppressor genes Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings Fig. 18-22 Colon EFFECTS OF MUTATIONS 1 Loss of tumorsuppressor gene Colon wall APC (or other) Normal colon epithelial cells 4 Loss of tumor-suppressor gene p53 2 Activation of ras oncogene Small benign growth (polyp) 3 Loss of tumor-suppressor gene DCC 5 Additional mutations Larger benign growth (adenoma) Malignant tumor (carcinoma) Inherited Predisposition and Other Factors Contributing to Cancer • Individuals can inherit oncogenes or mutant alleles of tumor-suppressor genes • Inherited mutations in the tumor-suppressor gene adenomatous polyposis coli are common in individuals with colorectal cancer • Mutations in the BRCA1 or BRCA2 gene are found in at least half of inherited breast cancers Copyright © 2008 Pearson Education Inc., publishing as Pearson Benjamin Cummings