Regulation of Gene Expression

Regulation of Gene Expression
Chapter 18 Regulation of Gene Expression

C. pancreas beta cells (and alpha)
Concept Check Which of the following cells would likely express the genes that code for the hormone insulin? muscle cell white blood cell pancreas beta cells all of these cells none of these cells A. muscle cell B. white blood cell C. pancreas beta cells (and alpha) Correct Answer: c

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 Gene expression in bacteria is controlled by the operon model Trp operon animation -

Control of Gene Expression in Prokaryotes

Regulation of gene expression
Figure 18.2 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

What does the operon model attempt to explain?
the coordinated control of gene expression in bacteria bacterial resistance to antibiotics how genes move between homologous regions of DNA the mechanism of viral attachment to a host cell horizontal transmission of plant viruses Answer: a

Operons: The Basic Concept
An operon is the entire stretch of DNA that includes the operator, the promoter, and the genes that they control A cluster of functionally related genes under co-ordinated control by a single “on-off switch” A segment of DNA - operator - usually positioned within the promoter is the switch Switched off by repressor – a protein product of a separate gene that prevents gene transcription by binding to the operator and blocking RNA polymerase – can involve co-repressor

Operon What elements from the following list constitute a bacterial operon?
repressor gene promoter inducer All of the above Answer: b

Polypeptide subunits that make up enzymes for tryptophan synthesis
Figure 18.3a trp operon Promoter Promoter Genes of operon DNA trpR trpE trpD trpC trpB trpA Operator Regulatory gene RNA polymerase Start codon Stop codon 3 mRNA 5 mRNA 5 E D C B A Protein Inactive repressor Figure 18.3 The trp operon in E. coli: regulated synthesis of repressible enzymes. Polypeptide subunits that make up enzymes for tryptophan synthesis (a) Tryptophan absent, repressor inactive, operon on

Tryptophan (corepressor)
Figure 18.3b-2 DNA No RNA made mRNA Protein Active repressor Figure 18.3 The trp operon in E. coli: regulated synthesis of repressible enzymes. Tryptophan (corepressor) (b) Tryptophan present, repressor active, operon off

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 – example the trp operon An inducible operon is one that is usually off; a molecule called an inducer inactivates the repressor and turns on transcription – example the lac operon

(a) Lactose absent, repressor active, operon off
Figure 18.4a Regulatory gene Promoter Operator DNA DNA lacI lacZ 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

Each of a group of bacterial cells has a mutation in its lac operon
Each of a group of bacterial cells has a mutation in its lac operon. Which of these will make it impossible for the cell to metabolize lactose? mutation in lacZ (β-galactosidase gene) mutation in lacI (cannot bind to operator) mutation in operator (cannot bind repressor) mutation in lacI (cannot bind inducer) Answer: a

Allolactose (inducer)
Figure 18.4b lac operon DNA lacI lacZ lacY lacA RNA polymerase 3 mRNA mRNA 5 5 -Galactosidase Permease Transacetylase Protein Figure 18.4 The lac operon in E. coli: regulated synthesis of inducible enzymes. Inactive repressor Allolactose (inducer) (b) Lactose present, repressor inactive, operon on

Positive Gene Regulation
Promoter DNA lacI lacZ CAP-binding site RNA polymerase binds and transcribes Operator Active CAP cAMP Figure 18.5 Positive control of the lac operon by catabolite activator protein (CAP). Inactive lac repressor Inactive CAP Allolactose (a) Lactose present, glucose scarce (cAMP level high): abundant lac mRNA synthesized

RNA polymerase less likely to bind
Figure 18.5b Promoter DNA lacI lacZ Operator CAP-binding site RNA polymerase less likely to bind Inactive CAP Inactive lac repressor Figure 18.5 Positive control of the lac operon by catabolite activator protein (CAP). (b) Lactose present, glucose present (cAMP level low): little lac mRNA synthesized

Positive Gene Regulation
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 (cAMP) 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

A specific gene is known to code for three different but related proteins. This could be due to which of the following? premature mRNA degradation alternative RNA splicing use of different enhancers protein degradation differential transport Answer: b

Control of Gene Expression in Eukaryotes

Other Steps in Gene Expression
Telomerase Functionhttp://highered.mcgraw-hill.com/sites/ /student_view0/animations.html# 13-16 Translation Initiation 13-18 Translation Elongation 13-19 Translation Termination

Eukaryotic gene expression is regulated at many stages
Signal NUCLEUS Chromatin Chromatin modification: DNA unpacking involving histone acetylation and DNA demethylation DNA Eukaryotic gene expression is regulated at many stages Gene available for transcription Gene Transcription RNA Exon Primary transcript Intron Figure 18.6 Stages in gene expression that can be regulated in eukaryotic cells. RNA processing Tail mRNA in nucleus Cap Transport to cytoplasm CYTOPLASM

Protein processing, such as cleavage and chemical modification
CYTOPLASM mRNA in cytoplasm Translation Degradation of mRNA Polypeptide Protein processing, such as cleavage and chemical modification Active protein Degradation of protein Figure 18.6 Stages in gene expression that can be regulated in eukaryotic cells. Transport to cellular destination Cellular function (such as enzymatic activity, structural support)

Regulation of Chromatin Structure http://www. allthingsscience
Histone tails DNA double helix Amino acids available for chemical modification Nucleosome (end view) (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

DNA Methylation Addition of methyl groups to certain bases in DNA - reduces transcription in some species Can cause long-term inactivation of genes in cellular differentiation In genomic imprinting, methylation regulates expression of either the maternal or paternal alleles of certain genes at the start of development

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 Epigenetics animation clips for Windfall Films - Scientific American Animation -

Approximately what proportion of the DNA in the human genome codes for proteins or functional RNA?
83% 46% 32% 13% 1.5% Answer e

Enhancer (distal control elements) Proximal control elements
Figure Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Transcription start site Transcription termination region DNA Exon Intron Exon Intron Exon Upstream Downstream Promoter Transcription Poly-A signal Primary RNA transcript (pre-mRNA) Exon Intron Exon Intron Exon Cleaved 3 end of primary transcript 5 RNA processing Intron RNA Figure 18.8 A eukaryotic gene and its transcript. Coding segment mRNA G P P P AAA  AAA 3 Start codon Stop codon 5 Cap 5 UTR 3 UTR Poly-A tail

Distal control element Enhancer TATA box General transcription factors
Figure Promoter Activators Gene DNA Distal control element Enhancer TATA box General transcription factors DNA- bending protein Group of mediator proteins RNA polymerase II Figure A model for the action of enhancers and transcription activators. RNA polymerase II Transcription initiation complex RNA synthesis

Albumin gene expressed
Figure 18.11a Enhancer Promoter Control elements LIVER CELL NUCLEUS Albumin gene Available activators Crystallin gene Albumin gene expressed Figure Cell type–specific transcription. Crystallin gene not expressed (a) Liver cell

Albumin gene not expressed
Figure 18.11b Enhancer Promoter Control elements LENS CELL NUCLEUS Albumin gene Available activators Crystallin gene Albumin gene not expressed Figure Cell type–specific transcription. Crystallin gene expressed (b) Lens cell

Primary RNA transcript
Figure 18.13 Exons DNA 1 2 3 4 5 Troponin T gene Primary RNA transcript 1 2 3 4 5 Figure Alternative RNA splicing of the troponin T gene. RNA splicing mRNA or 1 2 3 5 1 2 4 5

mRNA Degradation The life span of mRNA molecules in the cytoplasm is a key to determining protein synthesis Eukaryotic mRNA is more long lived than prokaryotic mRNA Nucleotide sequences that influence the lifespan of mRNA in eukaryotes reside in the untranslated region (UTR) at the 3 end of the molecule

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 For example, translation initiation factors are simultaneously activated in an egg following fertilization

Protein Processing and Degradation
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 Proteasome and ubiquitin to be recycled Ubiquitin Proteasome Protein to be degraded Ubiquitinated protein Protein fragments (peptides) Protein entering a proteasome

RNA is a versatile molecule that governs our life

Noncoding RNAs play multiple roles in controlling gene expression
Only a small fraction of DNA codes for proteins, and a very small fraction of the non-protein-coding DNA consists of genes for RNA such as rRNA and tRNA A significant amount of the genome may be transcribed into noncoding RNAs (ncRNAs) Noncoding RNAs regulate gene expression at two points: mRNA translation and chromatin configuration MicroRNAs (miRNAs) are small single-stranded RNA molecules that can bind to mRNA These can degrade mRNA or block its translation

(a) Primary miRNA transcript miRNA miRNA- protein complex
Figure 18.15 Hairpin Hydrogen bond miRNA Dicer 5 3 (a) Primary miRNA transcript miRNA miRNA- protein complex Figure Regulation of gene expression by miRNAs. mRNA degraded Translation blocked (b) Generation and function of miRNAs

RNAi is caused by small interfering RNAs (siRNAs)
The phenomenon of inhibition of gene expression by RNA molecules is called RNA interference (RNAi) RNAi is caused by small interfering RNAs (siRNAs) siRNAs and miRNAs are similar but form from different RNA precursors

(a) Cytoplasmic determinants in the egg
Figure 18.17a (a) Cytoplasmic determinants in the egg Unfertilized egg Sperm Nucleus Fertilization Molecules of two different cytoplasmic determinants Zygote (fertilized egg) Figure Sources of developmental information for the early embryo. Mitotic cell division Two-celled embryo

(b) Induction by nearby cells
Figure 18.17b (b) Induction by nearby cells Early embryo (32 cells) NUCLEUS Signal transduction pathway Figure Sources of developmental information for the early embryo. Signal receptor Signaling molecule (inducer)

Master regulatory gene myoD
Figure 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)

Certain Forms of Gene Regulation

Egg developing within ovarian follicle Nucleus
Figure 18.19 Head Thorax Abdomen Follicle cell 1 Egg developing within ovarian follicle Nucleus Egg 0.5 mm Nurse cell Dorsal Right 2 Unfertilized egg Egg shell BODY AXES Anterior Posterior Depleted nurse cells Left Ventral Fertilization (a) Adult Laying of egg 3 Fertilized egg Embryonic development Figure Key developmental events in the life cycle of Drosophila. 4 Segmented embryo 0.1 mm Body segments Hatching 5 Larval stage (b) Development from egg to larva

Concept Check Which of the following development events triggers the definition of the head and tail regions in a fruit fly? activation of the homeotic genes in the developing embryo accumulation of “head” mRNA in one end of the unfertilized egg gravitational response in the developing embryo Correct Answer: b

Genetic Analysis of Early Development
Edward B. Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus - Nobel 1995 Prize for homeotic genes, which control pattern formation in late embryo, larva, and adult stages Eye Leg Antenna Wild type Mutant

Head Tail Wild-type larva 250 m Tail Tail Mutant larva (bicoid) A8 T1
Figure 18.21 Head Tail A8 T1 T2 T3 A7 A6 A1 A5 A2 A4 A3 Wild-type larva 250 m Tail Tail Figure Effect of the bicoid gene on Drosophila development. A8 A8 A7 A6 A7 Mutant larva (bicoid)

Fertilization, translation of bicoid mRNA
Figure 18.22 RESULTS 100 m Anterior end Fertilization, translation of bicoid mRNA Bicoid mRNA in mature unfertilized egg Bicoid protein in early embryo Figure Inquiry: Is Bicoid a morphogen that determines the anterior end of a fruit fly? Bicoid mRNA in mature unfertilized egg Bicoid protein in early embryo

The bicoid research is important for three reasons
– It identified a specific protein required for some early steps in pattern formation – It increased understanding of the mother’s role in embryo development – It demonstrated a key developmental principle that a gradient of molecules can determine polarity and position in the embryo

within a control element
Figure 18.23 Proto-oncogene DNA Translocation or transposition: gene moved to new locus, under new controls Gene amplification: multiple copies of the gene 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

Protein kinases (phosphorylation cascade) Receptor
Figure 18.24a 1 Growth factor MUTATION Ras Hyperactive Ras protein (product of oncogene) issues signals on its own. 3 G protein GTP Ras P P P P GTP P P 4 2 Protein kinases (phosphorylation cascade) Receptor NUCLEUS 5 Transcription factor (activator) DNA Figure Signaling pathways that regulate cell division. Gene expression Protein that stimulates the cell cycle (a) Cell cycle–stimulating pathway

Protein that inhibits the cell cycle
Figure 18.24b 2 Protein kinases MUTATION Defective or missing transcription factor, such as p53, cannot activate transcription. 3 UV light Active form of p53 1 DNA damage in genome DNA Figure Signaling pathways that regulate cell division. Protein that inhibits the cell cycle (b) Cell cycle–inhibiting pathway

Protein overexpressed Protein absent
Figure 18.24c EFFECTS OF MUTATIONS Protein overexpressed Protein absent Cell cycle overstimulated Increased cell division Cell cycle not inhibited Figure Signaling pathways that regulate cell division. (c) Effects of mutations

Which of the following would not typically cause a proto-oncogene to become an oncogene?
gene suppression translocation amplification point mutation retroviral activation Answer: a

The Multistep Model of Cancer Development
Colon 1 Loss of tumor- suppressor gene APC (or other) 4 Loss of tumor- suppressor gene p53 2 Activation of ras oncogene 3 Loss of tumor- suppressor gene DCC Additional mutations 5 Colon wall 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)

Table 11.2 Cancer in the United States (Ranked by Number of Cases)

Figure 11.UN09 Proto-oncogene (normal) Oncogene Mutation Normal
protein Mutant protein Out-of-control growth (leading to cancer) Normal regulation of cell cycle Normal growth-inhibiting protein Defective protein Figure 11.UN09 Summary: genes that cause cancer Mutation Tumor-suppressor gene (normal) Mutated tumor-suppressor gene Figure 11.UN09

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