REGULATION OF GENE

EXPRESSION

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SIGNIFICANCE OF GENE EXPRESSION
REGULATION IN MEDICINE
• Example:

• Regulation of gene expression: gene for erythropoietin (induction

of transcription)
• Situation: hypoxia (activation of HIF)

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REGULATION OF GENE EXPRESSION:

1. Gene expression
2. Levels of the regulation of gene expression
3. Genome
4. Transcription
5. Posttranscriptional modifications
6. mRNA
7. Translation
8. Posttranslational modifications
9. Protein degradation

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1. GENE EXPRESSION:

Gene expression: a process in which the genetic information saved in

individual genes is converted into functional molecules of encoded
proteins.

The expression of individual genes is regulated within cells.

→
Effective functioning of cells/organisms (adaptation to changes of
environmental conditions, differentiation into various cell types)

Cell differentiation: the expression of different genes leads to differing

cell types. [FIG.]

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2. LEVELS OF THE REGULATION OF GENE
EXPRESSION:
• Genome (DNA)
• Transcription (DNA → RNA/primary transcript)
• Posttranscriptional modifications (RNA/primary transcript →
mRNA)
• mRNA (mRNA)
• Translation (mRNA → polypeptide chain)
• Posttranslational modifications (polypeptide chain → functional
protein)
• Protein degradation (functional protein → degraded protein)

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3. GENOME:

The status of genome affects the expression of genes:

• Gene amplification
• Genome rearrangement
• Chromosome condensation/decondensation
• DNA methylation

• Gene amplification: increase of the number of copies of certain

gene

• Gene rearrangement: transposons, genes coding for

immunoglobulins

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• Chromosome condensation/decondensation: higher degree of
condensation → DNA less accessible for transcription factors and RNA
polymerase (heterochromatin, X chromosome).
Histone deacetylase: it removes the acetyl group from histone →
DNA less accessible for transcription.
Histone acetyltransferase: it binds acetyl group to histone → DNA
more accessible for transcription. [FIG.]

• DNA methylation: higher degree of methylation → lower degree of

gene expression. Generally, genes with methylated DNA are not
expressed (X chromosome, genomic imprinting).
Methylase: it catalyzes the methylation of cytosine in DNA (5-
methylcytosine).
Demethylase: it catalyzes the demethylation of cytosine. [FIG.] [FIG.]

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Figure 1 | The nucleosome and histone modification by acetylation/deacetylation. (a)
Nucleosome is the main structural unit of chromatin and is constituted by a core of histone
proteins and a coil of DNA. Acetyl groups bind lysine residue on histones. (b) Histone
modification by acetylation/deacetylation represents a specific epigenetic mechanism that
regulates chromatin remodelling and thereby influences gene transcription. In particular, the
addition of acetyl groups on lysine residues (acetylation), given by histone acetyltransferases
(HAT), reduces the affinity between histones and DNA, loosens the chromatin and activates
transcription factors. On the other hand, deacetylation induced by histone deacetylases (HDAC)
leads to a more compact status of chromatin and then to repression of gene transcription.
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• Chromosome condensation/decondensation: higher degree of
condensation → DNA less accessible for transcription factors and RNA
polymerase (heterochromatin, X chromosome).
Histone deacetylase: it removes the acetyl group from histone →
DNA less accessible for transcription.
Histone acetyltransferase: it binds acetyl group to histone → DNA
more accessible for transcription. [FIG.]

• DNA methylation: higher degree of methylation → lower degree of

gene expression. Generally, genes with methylated DNA are not
expressed (X chromosome, genomic imprinting).
Methylase: it catalyzes the methylation of cytosine in DNA (5-
methylcytosine).
Demethylase: it catalyzes the demethylation of cytosine. [FIG.] [FIG.]

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Figure 7-80 How DNA methylation patterns are faithfully inherited.

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4. TRANSCRIPTION:

Regulation of transcription: a key step in the regulation of individual

gene expression usually mediated by the
binding of specific proteins to specific DNA
sequences

Regulatory DNA sequences: DNA sequences (10-10000 base pairs)

which are involved in switching particular genes on or off.
• Promoter
• Other regulatory DNA sequences (enhancer)

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Proteins regulating gene transcription: they are involved in the
regulation of particular gene expression by binding to regulatory DNA
sequences.
• General transcription factors
• Specific transcription factors

Proteins regulating gene transcription contain several DNA-binding

motifs:
• Homeodomain
• Zinc finger
• Leucine zipper [FIG.] [FIG.]

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Homeodomain

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Zinc fingers Leucine zipper
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The regulation of transcription in procaryotic cells:

Operon: a cluster of genes transcribed from a single promoter. [FIG.]

Repressor & operator (binding site for repressor within promoter) –
tryptophan operon [FIG.]
Activator & binding site for activator – lac operon [FIG.]

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The regulation of transcription in procaryotic cells:

Operon: a cluster of genes transcribed from a single promoter. [FIG.]

Repressor & operator (binding site for repressor within promoter) –
tryptophan operon [FIG.]
Activator & binding site for activator – lac operon [FIG.]

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The regulation of transcription in procaryotic cells:

Operon: a cluster of genes transcribed from a single promoter. [FIG.]

Repressor & operator (binding site for repressor within promoter) –
tryptophan operon [FIG.]
Activator & binding site for activator – lac operon [FIG.]

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The regulation of transcription in eucaryotic cells:

General transcription factors: they assemble with RNA polymerase

at the promoter of gene via binding to TATA box.
TATA box: a DNA sequence within the promoter which mostly contains
T and A [FIG.]
Activator & enhancer (binding site for activator) – activation at a
distance [FIG.]
Combinatorial control: several regulatory proteins work together to
control the expression of particular gene. [FIG.]

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The regulation of transcription in eucaryotic cells:

General transcription factors: they assemble with RNA polymerase

at the promoter of gene via binding to TATA box.
TATA box: a DNA sequence within the promoter which mostly contains
T and A [FIG.]
Activator & enhancer (binding site for activator) – activation at a
distance [FIG.]
Combinatorial control: several regulatory proteins work together to
control the expression of particular gene. [FIG.]

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The regulation of transcription in eucaryotic cells:

General transcription factors: they assemble with RNA polymerase

at the promoter of gene via binding to TATA box.
TATA box: a DNA sequence within the promoter which mostly contains
T and A [FIG.]
Activator & enhancer (binding site for activator) – activation at a
distance [FIG.]
Combinatorial control: several regulatory proteins work together to
control the expression of particular gene. [FIG.]

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5. POSTTRANSCRIPTIONAL MODIFICATIONS:

RNA capping and RNA polyadenylation increase the stability of

mRNA.

Posttranscriptional modifications affecting gene expression:

• Alternative splicing:
it allows that several proteins are encoded by the same gene (the
employment of various exons of the gene to form mRNA)
different proteins from the same gene: differing cell types or
differing stages of the development [FIG.]

• RNA editing :
an insertion or deletion of nucleotides or a substitution of
nucleotides in transcribed RNA
change of transcribed genetic information
→
appearance of new initiation and stop codons
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5. POSTTRANSCRIPTIONAL MODIFICATIONS:

RNA capping and RNA polyadenylation increase the stability of

mRNA.

Posttranscriptional modifications affecting gene expression:

• Alternative splicing:
it allows that several proteins are encoded by the same gene (the
employment of various exons of the gene to form mRNA)
different proteins from the same gene: differing cell types or
differing stages of the development [FIG.]

• RNA editing :
an insertion or deletion of nucleotides or a substitution of
nucleotides in transcribed RNA
change of transcribed genetic information
→
appearance of new initiation and stop codons
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6. mRNA:

mRNA degradation : the lifetime of mRNA affects the expression of

particular gene.

miRNA (microRNA): a short regulatory RNA which regulates gene

expression via the regulation of relevant mRNA degradation. [FIG.]

The lifetime of mRNA can be also regulated by nucleotide sequences in

the 3´ untranslated region of mRNA: e.g. IRE (iron responsive
element), to which IRP (iron regulatory protein) binds

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6. mRNA:

mRNA degradation : the lifetime of mRNA affects the expression of

particular gene.

miRNA (microRNA): a short regulatory RNA which regulates gene

expression via the regulation of relevant mRNA degradation. [FIG.]

The lifetime of mRNA can be also regulated by nucleotide sequences in

the 3´ untranslated region of mRNA: e.g. IRE (iron responsive
element), to which IRP (iron regulatory protein) binds

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7. TRANSLATION:

Translation can be regulated by specific protein binding to mRNA.

[FIG.]

As an example, we can mention IRE in the 5´ untranslated region of

mRNA to which IRP binds (translation is blocked).

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7. TRANSLATION:

Translation can be regulated by specific protein binding to mRNA.

[FIG.]

As an example, we can mention IRE in the 5´ untranslated region of

mRNA to which IRP binds (translation is blocked).

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8. POSTTRANSLATIONAL MODIFICATIONS:
Posttranslational modifications of polypeptide chain involve several
mechanisms including the cleavage of the chain and the binding of
molecules:

• Removal of methionine from the N end

• Removal of signal sequence

• Proteolytic cleavage: the formation of functional protein by

cleavage of a precursor polypeptide chain (proinsulin → insulin).

• Formation of disulfide bonds: they are formed between adjacent

cysteines. They stabilize protein structure. [FIG.]

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• Chemical modification of amino acids:
phosphorylation (binding of phosphate)
hydroxylation (binding of –OH group)

• Glycosylation: binding of oligosaccharide chain (glycoproteins)

[FIG.] [FIG.]

• Binding of prosthetic group: prosthetic group (nonamino acid/

nonprotein molecule) can be required for the functioning of protein
(heme in hemoglobin).

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• Chemical modification of amino acids:
phosphorylation (binding of phosphate)
hydroxylation (binding of –OH group)

• Glycosylation: binding of oligosaccharide chain (glycoproteins)

[FIG.] [FIG.]

• Binding of prosthetic group: prosthetic group (nonamino acid/

nonprotein molecule) can be required for the functioning of protein
(heme in hemoglobin).

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9. PROTEIN DEGRADATION:

Protein degradation: a way how the amount of particular protein within

the cell can be regulated.
Most proteins in cells are degraded by proteasomes.

Proteasome: large complex of proteolytic enzymes forming kind of

cylinder. [FIG.]

Ubiquitin: small protein

proteins are marked for degradation by covalent binding of
ubiquitin [FIG.] [FIG.]

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9. PROTEIN DEGRADATION:

Protein degradation: a way how the amount of particular protein within

the cell can be regulated.
Most proteins in cells are degraded by proteasomes.

Proteasome: large complex of proteolytic enzymes forming kind of

cylinder. [FIG.]

Ubiquitin: small protein

proteins are marked for degradation by covalent binding of
ubiquitin [FIG.] [FIG.]

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Figure 3-69 The marking of proteins by ubiquitin. (A) The three-dimensional structure of
ubiquitin, a small protein of 76 amino acids. A family of special enzymes couples its
carboxyl end to the amino group of a lysine side chain in a target protein molecule,
forming an isopeptide bond. (B) Some modification patterns that have specific meanings
to the cell. Note that the two types of polyubiquitination differ in the way the ubiquitin
molecules are linked together. Linkage through Lys48 signifies degradation by the
proteasome (see Figure 6-84), whereas that through Lys63 has other meanings.
Ubiquitin markings are „read“ by proteins that specially recognize each type of
modification.
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Figure 6-84 Processive protein digestion by the proteasome.

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LITERATURE:

• Alberts B. et al.: Essential Cell Biology. Garland Science. New York

and London, pp. 258-259 & 269-293, 2010

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