1. Regulation of Gene Expression
Chapter 18
Regulation of Gene Expression

2. 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

3. 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

4. Operons: The Basic Concept
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
An operon is the entire stretch of DNA that includes the operator, the promoter, and the genes that they control

5. 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

6. The regulation of sugar metabolism such as lactose involves repression in the absence of lactose, and induction when lactose is present.
Fig The lactose operon in bacteria

7. 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

8. The regulation of amino acids such as arginine involves repression when arginine accumulates, and no repression when arginine is being used.
Fig Repressible operon

9. Concept 18.2 Eukaryotic Gene Expression
All organisms must regulate which genes are expressed at any given time
Are all genes turned on all the time?
In multicellular organisms gene expression is essential for cell specialization

10. Almost all the cells in an organism are genetically identical (excluding the gametes)
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

11. 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
Translation
Polypeptide
Protein processing
Active protein
Degradation
of protein
Transport to cellular
destination
Cellular function

12. 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

13. DNA methylation, the attachment of methyl groups (- CH3) to DNA bases after DNA synthesis, stops transcription of a gene.
Inactive DNA is generally highly methylated compared to DNA that is actively transcribed.
For example, the inactivated mammalian X chromosome in females is heavily methylated.
Genes are usually more heavily methylated in cells where they are not expressed.
Demethylating certain inactive genes turns them on.
However, there are exceptions to this pattern.

14. DNA Methylation
DNA methylation, the addition of methyl groups to certain bases in DNA, is associated with reduced transcription in some species
DNA methylation 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

15. (distal control elements)
Fig
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
Coding segment
mRNA 3
Start
codon
Stop
codon
5 Cap
5 UTR
3 UTR
Poly-A
tail

16. Enhancers and Specific 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
An activator is a protein that binds to an enhancer and stimulates transcription of a gene
Bound activators cause mediator proteins to interact with proteins at the promoter

17. Enhancer Promoter Albumin gene Control elements Crystallin gene
Fig
Enhancer
Promoter
Albumin gene
Control
elements
Crystallin gene
LIVER CELL
NUCLEUS
LENS CELL
NUCLEUS
Available
activators
Available
activators
Albumin gene
not expressed
Albumin gene
expressed
Crystallin gene
not expressed
Crystallin gene
expressed
(a) Liver cell
(b) Lens cell

18. RNA Processing
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

19. Exons DNA Troponin T gene Primary RNA transcript RNA splicing mRNA or
Fig
Exons
DNA
Troponin T gene
Primary
RNA
transcript
RNA splicing
mRNA or

20. Concept 18.4 Differential Gene Expression  Different Cell Types
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

21. The transformation from zygote to adult results from cell division, cell differentiation, and morphogenesis

22. Cell differentiation is the process by which cells become specialized in structure and function
The physical processes that give an organism its shape constitute morphogenesis
Differential gene expression results from genes being regulated differently in each cell type

23. Fig
Eye
Leg
Antenna
Wild type
Mutant

24. Concept 18.5: Cancer and Genes
Cancer is a disease in which cells escape from the control methods that normally regulate cell growth and division.
The agent of such changes can be random spontaneous mutations or environmental influences such as chemical carcinogens or physical mutagens.
Cancer-causing genes, oncogenes, were initially discovered in retroviruses, but close counterparts, proto-oncogenes were found in other organisms.

26. The products of proto-oncogenes are proteins that stimulate normal cell growth and division, have essential functions in normal cells.
An oncogene arises from a genetic change and leads to an increase in the proto-oncogene’s activity.

27. Mutations to genes whose normal products inhibit cell division, tumor-suppressor genes, contribute to cancer.
Any decrease in the normal activity of a tumor-suppressor protein may contribute to cancer.
Some tumor-suppressor proteins normally repair damaged DNA, preventing the accumulation of cancer-causing mutations.

28. Mutations in the p53 tumor suppressor gene occur in 50% of human cancers.
The tumor-suppressor protein encoded by the normal p53 gene is a transcription factor that promotes synthesis of growth-inhibiting proteins.
A mutation that knocks out the p53 gene can lead to excessive cell growth and cancer.

29. The p53 protein is a transcription factor for several genes.
Damage to the cell’s DNA acts as a signal that leads to expression of the p53 gene.
The p53 protein is a transcription factor for several genes.
It can activate the p21 gene, which halts the cell cycle.
It can turn on genes involved in DNA repair.
When DNA damage is irreparable, the p53 protein can activate “suicide genes” whose protein products cause cell death by apoptosis.

30. 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

31. EFFECTS OF MUTATIONS Fig. 18-22 Colon 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
Normal colon
epithelial cells
Small benign
growth (polyp)
Larger benign
growth (adenoma)
Malignant tumor
(carcinoma)

32. 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

33. You should now be able to:
Describe the concept of an operon and the function of the operator and repressor
Explain the adaptive advantage of grouping bacterial genes into an operon
Explain how repressible and inducible operons differ
Show how DNA methylation and histone acetylation affect chromatin structure and the regulation of transcription
Explain the role of promoters, enhancers, activators, and repressors in transcription control
Show how mutations in tumor-suppressor genes can contribute to cancer