1. Regulation of Gene Expression11
Regulation of Gene Expression

2. Chapter 11 Regulation of Gene Expression
Key Concepts
11.1 Several Strategies Are Used to Regulate Gene Expression
11.2 Many Prokaryotic Genes Are Regulated in Operons
11.3 Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
11.4 Eukaryotic Gene Expression Can Be Regulated after Transcription

3. Chapter 11 Opening Question
How does CREB regulate the expression of many genes?

4. Concept 11.1 Several Strategies Are Used to Regulate Gene Expression
Gene expression is tightly regulated.
Gene expression may be modified to counteract environmental changes, or gene expression may change to alter function in the cell.
Constitutive proteins are actively expressed all the time.
Inducible genes are expressed only when their proteins are needed by the cell.
See Chapters 5, 7, and 9

5. Figure 11.1 Potential Points for the Regulation of Gene Expression

6. Concept 11.1 Several Strategies Are Used to Regulate Gene Expression
Genes can be regulated at the level of transcription.
Gene expression begins at the promoter where transcription is initiated.
In selective gene transcription a “decision” is made about which genes to activate.
Two types of regulatory proteins—also called transcription factors—control whether a gene is active.
See Chapter 10
LINK You may wish to review the processes of transcription described in Concept 10.2

7. Concept 11.1 Several Strategies Are Used to Regulate Gene Expression
These proteins bind to specific DNA sequences near the promoter:
Negative regulation—a repressor protein prevents transcription
Positive regulation—an activator protein binds to stimulate transcription

8. Figure 11.2 Positive and Negative Regulation (Part 1)

9. Figure 11.2 Positive and Negative Regulation (Part 2)

10. Concept 11.1 Several Strategies Are Used to Regulate Gene Expression
Acellular viruses use gene regulation to take over host cells.
A phage injects a host cell with nucleic acid that takes over synthesis.
New viral particles (virions) appear rapidly and are soon released from the lysed cell.
This lytic cycle is a typical viral reproductive cycle—in a lysogenic phase, the viral genome is incorporated into the host genome and is replicated too.
See Chapter 9
See Figure 9.2

11. Concept 11.1 Several Strategies Are Used to Regulate Gene Expression
A bacteriophage may contain DNA or RNA and may not have a lysogenic phase.
The lytic cycle has two stages:
Early stage—promoter in the viral genome binds host RNA polymerase and adjacent viral genes are transcribed
Early genes shut down transcription of host genes, and stimulate viral replication and transcription of viral late genes.
Host genes are shut down by a posttranscriptional mechanism.
Viral nucleases digest the host’s chromosome for synthesis in new viral particles.

12. Concept 11.1 Several Strategies Are Used to Regulate Gene Expression
Late stage—viral late genes are transcribed
They encode the viral capsid proteins and enzymes to lyse the host cell and release new virions.
The whole process from binding and infection to release of new particles takes about 30 minutes.
VIDEO 11.1 Bacteriophage attack Escherichia coli

13. Figure 11.3 A Gene Regulation Strategy for Viral Reproduction

14. Concept 11.1 Several Strategies Are Used to Regulate Gene Expression
Human immunodeficiency virus (HIV) is a retrovirus with single-stranded RNA.
HIV is enclosed in a membrane from the previous host cell—it fuses with the new host cell’s membrane.
After infection, RNA-directed DNA synthesis is catalyzed by reverse transcriptase.
Two strands of DNA are synthesized and reside in the host’s chromosome as a provirus.

15. Figure 11.4 The Reproductive Cycle of HIV

16. Concept 11.1 Several Strategies Are Used to Regulate Gene Expression
Host cells have systems to repress the invading viral genes.
One system uses transcription “terminator” proteins that interfere with RNA polymerase.
HIV counteracts this negative regulation with Tat (Transactivator of transcription), which allows RNA polymerase to transcribe the viral genome.

17. Figure 11.5 Regulation of Transcription by HIV (Part 1)

18. Figure 11.5 Regulation of Transcription by HIV (Part 2)

19. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
Prokaryotes conserve energy by making proteins only when needed.
In a rapidly changing environment, the most efficient gene regulation is at the level of transcription.
E. coli must adapt quickly to food supply changes. Glucose or lactose may be present.

20. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
Uptake and metabolism of lactose involve three proteins:
-galactoside permease—a carrier protein that moves sugar into the cell
-galactosidase—an enzyme that hydrolyses lactose
-galactoside transacetylase—transfers acetyl groups to certain -galactosides
If E. coli is grown with glucose but no lactose present, no enzymes for lactose conversion are produced.

21. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
If lactose is predominant and glucose is low, E. coli synthesizes all three enzymes.
If lactose is removed, synthesis stops.
A compound that induces protein synthesis is an inducer.
Gene expression and regulating enzyme activity are two ways to regulate a metabolic pathway.
See Chapter 3

22. Figure 11.6 Two Ways to Regulate a Metabolic Pathway

23. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
Structural genes specify primary protein structure—the amino acid sequence.
The three structural genes for lactose enzymes are adjacent on the chromosome, share a promoter, and are transcribed together.
Their synthesis is all-or-none.

24. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
A gene cluster with a single promoter is an operon—the one that encodes for the lactose enzymes is the lac operon.
An operator is a short stretch of DNA near the promoter that controls transcription of the structural genes.
Inducible operon—turned off unless needed
Repressible operon—turned on unless not needed

25. Figure 11.7 The lac Operon of E. coli

26. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
The lac operon is only transcribed when a -galactoside predominates in the cell:
A repressor protein is normally bound to the operator, which blocks transcription.
In the presence of a -galactoside, the repressor detaches and allows RNA polymerase to initiate transcription.
The key to this regulatory system is the repressor protein.
ANIMATED TUTORIAL 11.1 The lac Operon
APPLY THE CONCEPT Many prokaryotic genes are regulated in operons, which include regulatory DNA sequences

27. Figure 11.8 The lac Operon: An Inducible System (Part 1)

28. Figure 11.8 The lac Operon: An Inducible System (Part 2)

29. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
A repressible operon is switched off when its repressor is bound to its operator.
However, the repressor only binds in the presence of a co-repressor.
The co-repressor causes the repressor to change shape in order to bind to the promoter and inhibit transcription.
Tryptophan functions as its own co- repressor, binding to the repressor of the trp operon.
ANIMATED TUTORIAL 11.2 The trp Operon

30. Figure 11.9 The trp Operon: A Repressible System (Part 1)

31. Figure 11.9 The trp Operon: A Repressible System (Part 2)

32. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
Difference in two types of operons:
In inducible systems—a metabolic substrate (inducer) interacts with a regulatory protein (repressor); the repressor cannot bind and allows transcription.
In repressible systems—a metabolic product (co-repressor) binds to regulatory protein, which then binds to the operator and blocks transcription.

33. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
Generally, inducible systems control catabolic pathways—turned on when substrate is available
Repressible systems control anabolic pathways—turned on until product concentration becomes excessive
LINK Review the descriptions of catabolic and anabolic reactions in Concept 2.5

34. Concept 11.2 Many Prokaryotic Genes Are Regulated in Operons
Sigma factors—other proteins that bind to RNA polymerase and direct it to specific promoters
Global gene regulation: Genes that encode proteins with related functions may have a different location but have the same promoter sequence—they are turned on at the same time.
Sporulation occurs when nutrients are depleted—genes are expressed sequentially, directed by a sigma factor.
See Chapter 10
LINK For more on sporulation as a survival strategy, see Concept 19.2

35. Table 11.1 Transcription in Bacteria and Eukaryotes

36. Transcription factors act at eukaryotic promoters.
Concept Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
Transcription factors act at eukaryotic promoters.
Each promoter contains a core promoter sequence where RNA polymerase binds.
TATA box is a common core promoter sequence—rich in A-T base pairs.
Only after general transcription factors bind to the core promoter, can RNA polymerase II bind and initiate transcription.
ANIMATED TUTORIAL 11.3 Initiation of Transcription

37. Figure 11.10 The Initiation of Transcription in Eukaryotes (Part 1)

38. Figure 11.10 The Initiation of Transcription in Eukaryotes (Part 2)

39. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
Besides the promoter, other sequences bind regulatory proteins that interact with RNA polymerase and regulate transcription.
Some are positive regulators—activators; others are negative—repressors.
DNA sequences that bind activators are enhancers, those that bind repressors are silencers.
The combination of factors present determines the rate of transcription.

40. In-Text Art, Ch. 11, p. 216

41. Transcription factors recognize particular nucleotide sequences:
Concept Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
Transcription factors recognize particular nucleotide sequences:
NFATs (nuclear factors of activated T cells) are transcription factors that control genes in the immune system.
They bind to a recognition sequence near the genes’ promoters.
The binding produces an induced fit—the protein changes conformation.
See Chapter 31
See Chapter 9

42. Figure 11.11 A Transcription Factor Protein Binds to DNA

43. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
Gene expression can be coordinated, even if genes are far apart on different chromosomes.
They must have regulatory sequences that bind the same transcription factors.
Plants use this to respond to drought—the scattered stress response genes each have a specific regulatory sequence, the dehydration response element.
During drought, a transcription factor changes shape and binds to this element.

44. Figure 11.12 Coordinating Gene Expression

45. Alterations can be passed on to daughter cells.
Concept Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
Gene transcription can also be regulated by reversible alterations to DNA or chromosomal proteins.
Alterations can be passed on to daughter cells.
These epigenetic changes are different from mutations, which are irreversible changes to the DNA sequence.
See Concept 9.3

46. Regions rich in C and G are called CpG islands—often in promoters
Concept Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
Some cytosine residues in DNA are modified by adding a methyl group covalently to the 5′ carbon—forms 5′- methylcytosine
DNA methyltransferase catalyzes the reaction—usually in adjacent C and G residues.
Regions rich in C and G are called CpG islands—often in promoters

47. Figure 11.13 DNA Methylation: An Epigenetic Change (Part 1)

48. Figure 11.13 DNA Methylation: An Epigenetic Change (Part 2)

49. This covalent change in DNA is heritable:
Concept Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
This covalent change in DNA is heritable:
When DNA replicates, a maintenance methylase catalyzes formation of 5′- methylcytosine in the new strand.
However, methylation pattern may be altered—demethylase can catalyze the removal of the methyl group.

50. Effects of DNA methylation:
Concept Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
Effects of DNA methylation:
Methylated DNA binds proteins that are involved in repression of transcription— genes tend to be inactive (silenced).
Patterns of DNA methylation may include large regions or whole chromosomes.

51. Two kinds of chromatin are visible during interphase:
Concept Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
Two kinds of chromatin are visible during interphase:
Euchromatin—diffuse and light-staining; contains DNA for mRNA transcription
Heterochromatin—condensed, dark- staining; contains genes not transcribed

52. A type of heterochromatin is the inactive X chromosome in mammals.
Concept Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
A type of heterochromatin is the inactive X chromosome in mammals.
Males (XY) and females (XX) contain different numbers of X-linked genes, yet for most genes transcription, rates are similar.
Early in development, one of the X chromosomes is inactivated—this Barr body is identifiable during interphase and can be seen in cells of human females.
See Chapter 8

53. Figure 11.14 X Chromosome Inactivation

54. Concept 11.3 Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
Another mechanism for epigenetic regulation is chromatin remodeling, or the alteration of chromatin structure.
Nucleosomes contain DNA and positively- charged histones in a tight complex, inaccessible to RNA polymerase.
Histone acetyltransferases change the charge by adding acetyl groups to the amino acids on the histone’s “tail.”
See Chapter 5

55. In-Text Art, Ch. 11, p. 219 (1)

56. Thus, histone acetyltransferases can activate transcription.
Concept Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
The change in charge opens up the nucleosomes as histone loses its affinity for DNA.
More chromatin remodeling proteins bind and open the DNA for gene expression.
Thus, histone acetyltransferases can activate transcription.

57. Figure 11.15 Epigenetic Remodeling of Chromatin for Transcription

58. Histone deacetylase is another kind of chromatin remodeling protein.
Concept Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
Histone deacetylase is another kind of chromatin remodeling protein.
It can remove the acetyl groups from the histones, repressing transcription.

59. Environment plays an important role in epigenetic modifications.
Concept Eukaryotic Genes Are Regulated by Transcription Factors and DNA Changes
Environment plays an important role in epigenetic modifications.
Even though they are reversible, some epigenetic changes can permanently alter gene expression patterns.
If the cells form gametes, the epigenetic changes can be passed on to the next generation.
Monozygotic twins show different DNA methylation patterns after living in different environments.

60. As introns and exons are spliced out, new proteins are made.
Concept Eukaryotic Gene Expression Can Be Regulated after Transcription
Eukaryotic gene expression can be regulated after the initial gene transcript is made.
Different mRNAs can be made from the same gene by alternative splicing.
As introns and exons are spliced out, new proteins are made.
This may be a deliberate mechanism for generating proteins with different functions, from a single gene.
See Figure 10.6

61. Examples of alternative splicing:
Concept Eukaryotic Gene Expression Can Be Regulated after Transcription
Examples of alternative splicing:
The HIV genome encodes nine proteins, but is transcribed as a single pre-mRNA.
In Drosophila the Sxl gene with four exons is spliced differently to produce different combinations in males and females.
See Figure 10.6

62. Figure 11.16 Alternative Splicing Results in Different Mature mRNAs and Proteins

63. Concept 11.4 Eukaryotic Gene Expression Can Be Regulated after Transcription
MicroRNAs(miRNAs)—small molecules of noncoding RNA—are important regulators of gene expression.
In C. elegans, lin-14 mutations cause the larvae to skip the first stage—thus the normal role for lin-14 is to be involved in stage one of development.
lin-4 mutations cause cells to repeat stage one events—thus the normal role for lin-4 is to negatively regulate lin-14, so that cells can progress to the next stage of development.
See Chapter 12

64. Concept 11.4 Eukaryotic Gene Expression Can Be Regulated after Transcription
lin-4 encodes not for a protein but for a 22- base miRNA that inhibits lin-14 expression posttranscriptionally by binding to its mRNA.
Many miRNAs have been described—once transcribed they are guided to a target mRNA to inhibit its translation and to degrade the mRNA.

65. Figure 11.17 mRNA Degradation Caused by MicroRNAs

66. mRNA translation can be regulated.
Concept Eukaryotic Gene Expression Can Be Regulated after Transcription
mRNA translation can be regulated.
Protein and mRNA concentrations are not consistently related—governed by factors acting after mRNA is made.
Cells either block mRNA translation or alter how long new proteins persist in the cell.

67. Three ways to regulate mRNA translation:
Concept Eukaryotic Gene Expression Can Be Regulated after Transcription
Three ways to regulate mRNA translation:
Inhibition of translation with miRNAs
Modification of the 5′ cap end of mRNA can be modified—if cap is unmodified mRNA is not translated.
Repressor proteins can block translation directly—translational repressors
APPLY THE CONCEPT Eukaryotic gene expression can be regulated transcriptionally and posttranscriptionally
See Concept 10.1

68. Figure 11.18 A Repressor of Translation

69. Figure 11.19 A Proteasome Breaks Down Proteins

70. Answer to Opening Question
The CREB family of transcription factors can activate or repress gene expression by binding to the cAMP response element (CRE) sequence found in the promoter region of many genes.
CREB binding is essential in many organs, including the brain, and has been linked to addiction and memory tasks as well as to metabolism.

71. Figure 11.20 An Explanation for Alcoholism?