AQA A-level Biology: Regulation of Gene Expression and Cancer (7402)

This guide covers AQA A-level Biology (7402) sections 3.8.2.2, Regulation of transcription and translation, and 3.8.2.3, Gene expression and cancer, from the AQA AS and A-level Biology specification for first teaching 2015. Both sections are A-level only and not AS content. The specification lists topics 5 to 8 for Paper 2 and topics 1 to 8 for Paper 3, so this content can appear on either. Other pages in this unit: the revision notes and the practice questions. Course pages: AQA A-level Biology hub and the printable checklist. To find weak spots first, try the free diagnostics.

All data sets in this guide are invented for teaching. They are not results from real studies.

What the specification asks for

Statement	What you must be able to do
3.8.2.2 Transcription factors	Explain how a transcription factor moving from cytoplasm to nucleus stimulates or inhibits transcription of target genes; use oestrogen as the example
3.8.2.2 Epigenetics	Define it; explain how increased DNA methylation or decreased histone acetylation inhibits transcription; link it to disease, especially cancer
3.8.2.2 RNA interference	Explain how translation of mRNA can be inhibited by RNAi
3.8.2.2 Skills	Interpret data from investigations into gene expression; evaluate data on genetic and environmental influences on phenotype
3.8.2.3 Tumours	State the main characteristics of benign and malignant tumours
3.8.2.3 Genes and cancer	Explain the roles of tumour suppressor genes, oncogenes, abnormal methylation, and raised oestrogen in some breast cancers
3.8.2.3 Skills	Evaluate evidence for genetic and environmental correlations with cancer; interpret information on using oncogene and tumour suppressor knowledge in prevention, treatment and cure

Transcription factors and oestrogen

In eukaryotes a gene is not transcribed all the time. Transcription factors are proteins that bind to specific base sequences of DNA near a target gene. Some stimulate transcription, by helping RNA polymerase to bind. Others inhibit it. The specification describes factors that move from the cytoplasm into the nucleus, so a gene can be switched by a signal that arrives at the cell.

Oestrogen is a steroid hormone, so it is lipid-soluble and diffuses through the phospholipid bilayer of the cell-surface membrane. The sequence is:

1. Oestrogen diffuses into the cell and binds to a specific receptor in the cytoplasm. Only cells that have this receptor respond.
2. Binding changes the shape of the receptor, forming a hormone-receptor complex that now acts as a transcription factor.
3. The complex enters the nucleus through a nuclear pore.
4. It binds to a specific base sequence next to the target gene.
5. It stimulates transcription: RNA polymerase can bind and make mRNA, which is translated into a protein.

The same pattern can work in reverse. A different transcription factor can bind and stop RNA polymerase attaching, so the gene is inhibited. In your answer, always say which gene is switched, which molecule binds, and what happens to RNA polymerase.

Worked example: reading an expression experiment

Cells with oestrogen receptors were grown with and without oestrogen, and the mRNA from one target gene was measured (arbitrary units).

Condition	mRNA level
Receptor-containing cells, no oestrogen	12
Receptor-containing cells, oestrogen added	138
Cells lacking the receptor, no oestrogen	11
Cells lacking the receptor, oestrogen added	13
Receptor-containing cells, oestrogen plus receptor-blocking drug	15

Percentage increase with oestrogen: (138 − 12) / 12 × 100 = 1050%. The level is 11.5 times higher.

Interpretation: oestrogen increases transcription of the gene (138 against 12). The cells without the receptor barely change (11 to 13), so the receptor is needed. The blocking drug keeps the level near the starting value, which supports the idea that oestrogen must bind the receptor. The data show the effect on mRNA, not directly on transcription rate, because mRNA level also depends on how fast mRNA breaks down.

Epigenetics

Epigenetics involves heritable changes in gene function without changes to the base sequence of DNA. The changes are caused by environmental changes and they inhibit transcription. The specification names two routes.

Increased DNA methylation. Methyl groups are added to bases in DNA, most often cytosine. The methylated region is not transcribed, because transcription factors cannot bind as easily and the DNA packs more tightly.

Decreased histone acetylation. DNA wraps around histone proteins. Histones are positively charged, so they attract the negatively charged phosphate groups of DNA. Acetylation of histones reduces this attraction. When acetylation decreases, the histones keep a stronger hold, the DNA is tightly wound, and transcription factors and RNA polymerase cannot reach the gene. High acetylation gives looser DNA and transcription can occur.

Change	Effect on DNA packing	Effect on transcription
Increased methylation	Tighter, less accessible	Inhibited
Decreased acetylation	Histones hold DNA tightly	Inhibited
Increased acetylation	Looser	Possible

Because these marks are copied when cells divide, they are passed to daughter cells. This explains how a cell type keeps its identity. It also means that an environmental factor can have lasting effects. The base sequence is unchanged, so epigenetic change is not a mutation.

Worked example: methylation data

Gene G was studied in normal and tumour tissue.

Tissue	Promoter sites methylated (%)	mRNA from gene G (relative)
Normal	8	100
Tumour	74	6

Methylation is 74 / 8 = 9.25 times higher in the tumour. The mRNA falls by (100 − 6) / 100 × 100 = 94%. The two changes go together, so the data are consistent with methylation silencing gene G. They show a correlation, not proof of cause. A stronger test would remove the methyl groups and see whether mRNA recovers.

RNA interference

In eukaryotes and some prokaryotes, translation of mRNA can be inhibited by RNA interference (RNAi). The steps for small interfering RNA (siRNA) are:

1. Double-stranded RNA is cut into short lengths of siRNA by an enzyme.
2. One strand of the siRNA joins a protein complex.
3. The strand pairs by complementary base pairing with an mRNA that has the matching sequence.
4. The complex breaks down (hydrolyses) that mRNA.
5. The mRNA is not translated, so the protein is not made.

The gene is still transcribed. The control is at translation, after transcription. RNAi is therefore different from methylation and acetylation, which act on DNA.

Worked example: matching siRNA to a target

A stretch of mRNA reads AUG GCU CCG UUA GCA. An siRNA guide strand is designed to pair with the 12 bases after AUG. Write each base’s partner (A with U, G with C):

mRNA bases 4 to 15: G C U C C G U U A G C A siRNA guide strand: C G A G G C A A U C G U

The siRNA is CGAGGCAAUCGU. If a protein level was 240 units in control cells and 54 units after siRNA treatment, the fall is (240 − 54) / 240 × 100 = 77.5%.

Benign and malignant tumours

A tumour is a mass of cells formed by uncontrolled cell division.

Feature	Benign	Malignant
Growth	Usually slow	Usually rapid
Boundary	Often a distinct border or capsule	Irregular; invades surrounding tissue
Spread	Does not spread to other tissues	Cells break away and form secondary tumours (metastasis), often via blood or lymph
Cells	Usually resemble normal cells of the tissue	Often less specialised, with abnormal nuclei
Danger	Usually less serious, but can press on organs	Often life-threatening

Oncogenes and tumour suppressor genes

Normal cells have genes that stimulate division and genes that slow it down. Cancer arises when this balance fails.

• Oncogenes are mutated or over-expressed forms of normal genes (proto-oncogenes) that stimulate cell division. A change makes the gene permanently active, or increases its expression, so cells divide without the usual signals. One altered allele can be enough.
• Tumour suppressor genes slow cell division, help to repair DNA mistakes, or cause cell death when damage cannot be repaired. When a mutation inactivates them, division is not held in check.

Abnormal methylation gives the same outcomes without a base change:

Gene type	Abnormal methylation	Result
Tumour suppressor gene	Hypermethylation (too much)	Gene silenced; no slowing of division
Oncogene (proto-oncogene)	Hypomethylation (too little)	Gene over-expressed; faster division

Oestrogen and breast cancer. In some breast cancers, cells with oestrogen receptors respond to oestrogen by dividing. Higher oestrogen concentrations, or a longer time at higher concentrations, stimulate more cell divisions. More divisions give more chances for mutation during DNA replication.

Using the knowledge for prevention, treatment and cure

You may be given information and asked to interpret it. Typical ideas:

• Prevention: genetic testing can show that a person carries a faulty tumour suppressor allele; they can then be screened sooner or take preventive steps.
• Treatment: a drug can block the oestrogen receptor, so oestrogen cannot stimulate division in receptor-positive cells; siRNA can be designed to lower the translation of an oncogene mRNA.
• Cure: treatments that reverse methylation or restore a working tumour suppressor gene aim to restore control of division.

Evaluating evidence on genetic risk

Worked example: carrier data

In a long-term study, 400 women with a variant allele and 800 without were followed to age 70. Cancer developed in 62 carriers and 41 non-carriers.

• Carriers: 62 / 400 × 100 = 15.5%.
• Non-carriers: 41 / 800 × 100 = 5.1% (5.125% before rounding).
• Relative risk: 15.5 / 5.125 = 3.0. Carriers are about three times as likely to be affected.

Evaluate: the group sizes are large, the groups were followed for the same time, and the effect is large. Still, 84.5% of carriers did not develop cancer, so the allele increases risk but does not decide the outcome. Check age, diet, smoking, family history and whether chance alone could explain the gap.

Worked example: twin data

Among 100 pairs of identical twins in which one twin had a cancer, the other twin also had it in 27 pairs. Among 100 pairs of non-identical twins, it was 13. Identical twins share all alleles, non-identical share about half. The higher figure for identical twins suggests a genetic influence. It is only 27%, so 73 of the identical pairs differ, and environment, chance and epigenetic differences must contribute.

Points for any evaluation

• Correlation does not prove cause.
• Check sample size, controls, age matching and confounding variables.
• State the size of the effect, not only its direction.
• Say what extra evidence would help.

Common errors

• Saying oestrogen “enters the nucleus”; the hormone-receptor complex does.
• Saying methylation changes the base sequence.
• Saying acetylation increases the positive charge on histones; it reduces it.
• Placing RNAi at transcription; it prevents translation.
• Calling every tumour cancerous; benign tumours do not spread.
• Dividing a change by the final figure; the starting figure is the divisor.

Official syllabus

AQA AS and A-level Biology specification (7401 and 7402), for first teaching 2015, sections 3.8.2.2 and 3.8.2.3 (version 1.5), published by AQA.