Regulation of Transcription — AQA A-level Biology

SPEC 3.8.2.2 - GENE EXPRESSION — REGULATION

Regulation of Gene Expression

Transcription factors, the oestrogen pathway, epigenetics (DNA methylation & histone acetylation), and RNA interference

Three Levels of Control

All cells in an organism contain the same genome, yet each cell type expresses a different subset of genes. The AQA specification focuses on three mechanisms by which gene expression is regulated:

MechanismLevel of controlEffect

Transcription factorsTranscriptional (DNA → mRNA)Stimulate or inhibit RNA polymerase binding; control rate of transcription

Epigenetic modifications (methylation, acetylation)Transcriptional (DNA access)Make DNA more or less accessible to transcription machinery — heritable

RNA interference (RNAi)Post-transcriptional (mRNA → protein)Small RNA molecules bind to mRNA, blocking or degrading it before translation

Key Principle

Mechanisms 1 and 2 act at the level of transcription — controlling whether mRNA is made. RNAi acts post-transcriptionally — the mRNA has been made but is prevented from being translated into protein.

Transcription Factors

Transcription Factor

A protein that binds to specific regulatory DNA sequences near a target gene and either stimulates or inhibits the binding of RNA polymerase, thereby controlling the rate of transcription of that gene.

How Transcription Factors Work

Transcription factors are proteins synthesised in the cytoplasm

In response to a signal, they move from the cytoplasm into the nucleus

In the nucleus they bind to specific regulatory DNA sequences (promoter or enhancer regions) near the target gene

Activator transcription factors: promote RNA polymerase binding → gene is transcribed at a higher rate

Repressor transcription factors: block RNA polymerase binding → gene is transcribed at a lower rate or not at all

Different combinations of transcription factors in different cell types determine which genes are expressed — this is how cell specialisation is maintained

Exam Tip

AQA mark schemes consistently reward "move from cytoplasm into nucleus" as a required step. Simply saying "bind to DNA" without stating the movement from cytoplasm to nucleus may lose marks.

Oestrogen: A Steroid Hormone Transcription Factor

The AQA specification uses oestrogen as the named example of a hormone that initiates transcription via a transcription factor mechanism.

Why Oestrogen Can Enter the Cell

Oestrogen is a steroid hormone — it is small, lipid-soluble, and non-polar. It can therefore diffuse directly across the phospholipid bilayer of the cell membrane without needing a receptor on the cell surface.

The Oestrogen Pathway — Step by Step

Oestrogen diffuses across the cell membrane (lipid-soluble)

Binds to a specific oestrogen receptor protein in the cytoplasm

The hormone-receptor complex forms and changes shape

The complex moves into the nucleus

The complex binds to specific regulatory DNA sequences (the oestrogen response element) near target genes

RNA polymerase is recruited → transcription of target genes is activated

Target gene mRNA is produced → translated into protein → cellular response

Oestrogen Pathway: Diagram

⚠️ EXAMINER ALERT: The oestrogen receptor is found in the cytoplasm, not on the cell surface. The hormone-receptor complex then moves into the nucleus. Do not describe oestrogen binding to a membrane receptor.

Epigenetics

Heritable changes in gene expression (or gene function) that do not involve changes to the base sequence of DNA. These changes are caused by modifications to DNA or to the histone proteins around which DNA is wound.

The Two Key Mechanisms (AQA Spec)

The AQA specification states that epigenetic changes inhibit transcription by:

Increased methylation of DNA — methyl groups (–CH₃) added to cytosine bases in the DNA

Decreased acetylation of histones — acetyl groups removed from histone proteins

Conversely, decreased methylation and increased acetylation allow or stimulate transcription.

Heritable Epigenetic Changes

When a cell divides by mitosis, methylation patterns and histone modifications are copied to the daughter cells

This allows differentiated cell types (e.g. liver cells, muscle cells) to maintain their identity across many cell generations

Epigenetic changes can also be influenced by environmental factors: diet, stress, ageing, toxins

DNA Methylation

The addition of methyl groups (–CH₃) to cytosine bases in DNA. Increased methylation of a gene's promoter region inhibits transcription — the gene is silenced.

Mechanism

Methyl groups are added to cytosine bases in the DNA by enzymes called DNA methyltransferases

Methylated promoter regions prevent transcription factors and RNA polymerase from binding to the DNA

Transcription cannot occur → the gene is silenced

Heavily methylated genes are described as being in a "closed" chromatin configuration — the DNA is wound tightly and inaccessible

Direction: Increased vs Decreased Methylation

Methylation levelEffect on transcriptionIncreased (hypermethylation)Inhibits / silences gene — transcription reduced or stoppedDecreased (hypomethylation)Allows / activates gene — transcription increased

Histone Acetylation

DNA in the nucleus is wound around proteins called histones. How tightly DNA wraps around histones determines whether RNA polymerase can access it.

Histone Acetylation

The addition of acetyl groups (–COCH₃) to histone proteins. Increased acetylation reduces the positive charge on histones, weakening their attraction to negatively charged DNA — the DNA uncoils and becomes more accessible to RNA polymerase, stimulating transcription.

Direction: Acetylation vs Deacetylation

Acetylation levelHistone-DNA interactionEffect on transcriptionIncreased acetylationHistones bind DNA less tightly → DNA uncoilsStimulates transcription (gene "open")Decreased acetylation (deacetylation)Histones bind DNA more tightly → DNA coils tightlyInhibits transcription (gene "closed")

⚠️ EXAMINER ALERT: The AQA spec states epigenetics inhibits transcription via decreased acetylation. Students often confuse the direction: more acetylation = more transcription. Less acetylation = histones grip tighter = less transcription. Remember: "Acetylation opens up."

Epigenetic Mechanisms: Visualised

Epigenetics & Disease

The AQA specification requires you to know the relevance of epigenetics to the development and treatment of disease, especially cancer.

Epigenetics in Cancer Development

Tumour suppressor genes: abnormal hypermethylation of the promoter → gene silenced → cannot stop uncontrolled cell division → contributes to cancer

Oncogenes: abnormal hypomethylation (reduced methylation) → gene overexpressed → promotes uncontrolled cell division → contributes to cancer

These epigenetic changes do not alter the DNA base sequence — but their effect (silencing or activating key cancer-related genes) is equivalent to a mutation in its consequences

Epigenetics in Disease Treatment

Reversibility: unlike DNA mutations, epigenetic modifications can potentially be reversed — offering therapeutic targets

Demethylating agents: drugs that reduce DNA methylation can reactivate silenced tumour suppressor genes

Histone deacetylase (HDAC) inhibitors: block removal of acetyl groups → keep chromatin open → restore expression of silenced genes

Both classes of drug are used or are in trials as anti-cancer therapies

Synoptic Link — Lesson 8.04

The detailed role of epigenetic changes in cancer (oncogenes, tumour suppressor genes, breast cancer and oestrogen) is covered in Lesson 8.04. At this stage, know the mechanism; the cancer application follows in the next lesson.

RNA Interference (RNAi)

A mechanism in which small RNA molecules bind to complementary sequences on target mRNA molecules, preventing translation. RNAi acts post-transcriptionally — the mRNA has been produced but is degraded or blocked from being translated.

How RNAi Works

Small RNA molecules are produced — either small interfering RNA (siRNA) or microRNA (miRNA)

These are short, double-stranded RNA molecules

One strand of the siRNA/miRNA binds to a complementary sequence on the target mRNA

The mRNA is either degraded (cleaved) or translation is blocked

The protein encoded by the target gene is not produced

Where RNAi Occurs

RNAi operates in eukaryotes and some prokaryotes. It is a natural gene-regulatory mechanism in cells, but siRNA molecules can also be introduced artificially to silence specific genes — this has major therapeutic potential for cancer, viral infections, and genetic diseases.

DEEP Framework: The Oestrogen Pathway

Exam question: "Describe how oestrogen stimulates the transcription of a target gene." [4 marks]

DDefine: Oestrogen is a steroid hormone (lipid-soluble) that acts via a transcription factor mechanism. It stimulates gene transcription by forming a hormone-receptor complex that moves into the nucleus and binds to regulatory DNA sequences near the target gene.

EExplain mechanism: Oestrogen diffuses across the phospholipid bilayer (lipid-soluble). Inside the cell, it binds to a specific oestrogen receptor protein in the cytoplasm. The hormone-receptor complex forms and moves into the nucleus. The complex binds to the oestrogen response element (regulatory DNA sequence) near the target gene.

EEvidence/consequence: RNA polymerase is recruited to the promoter and transcription of the target gene is activated. mRNA is produced and exported to the cytoplasm for translation into protein. This is how oestrogen controls the development of female secondary sexual characteristics and stimulates cell division in breast tissue.

PPractical/Quantitative: Drugs such as tamoxifen block the oestrogen receptor, preventing the hormone-receptor complex from forming. This is used to treat oestrogen-receptor-positive breast cancers — by blocking the receptor, tamoxifen prevents oestrogen from driving cell division gene transcription.

Examiner Alerts & Synoptic Links

⚠️ ERROR 1 — Oestrogen receptor location: Oestrogen binds to its receptor in the cytoplasm, not on the cell surface. Do not describe it as binding to a membrane receptor.

⚠️ ERROR 2 — Confusing acetylation direction: More acetylation = MORE transcription (DNA is more accessible). Less acetylation = LESS transcription (histones grip more tightly). Remember: "Acetylation opens up."

⚠️ ERROR 3 — Epigenetics definition: Epigenetic changes must be described as heritable changes in gene expression without changes to the base sequence of DNA. Simply saying "changes to gene expression" misses the key word "heritable" and the absence of DNA sequence change.

⚠️ ERROR 4 — RNAi level of control: RNAi acts post-transcriptionally — it does NOT prevent mRNA being produced; it prevents mRNA from being translated (or causes mRNA degradation). Do not say RNAi "prevents transcription."

Synoptic Link — Topic 1.04

Transcription factors are proteins. Their ability to bind specific DNA sequences depends on their tertiary structure — the shape of their DNA-binding domain must be complementary to the regulatory sequence. A mutation changing the transcription factor's shape would disrupt this interaction and alter gene expression.

Practice Question

(a) Explain what is meant by the term epigenetics. [2 marks]

(b) Describe how increased methylation of a gene's promoter region inhibits its transcription. [2 marks]

(c) A researcher treats cancer cells with a drug that inhibits histone deacetylase enzymes (enzymes that remove acetyl groups from histones). Explain how this treatment might reduce uncontrolled cell division. [3 marks]

a)

Epigenetics refers to heritable changes in gene expression that do not involve changes to the base sequence of DNA. These changes are caused by modifications to DNA (e.g. methylation) or to histones (e.g. acetylation). [2 marks — must include "heritable" and "no change to base sequence"]

b)

Methyl groups are added to cytosine bases in the promoter region. This prevents transcription factors and RNA polymerase from binding to the DNA. Transcription of the gene is therefore inhibited. [2 marks]

c)

Inhibiting histone deacetylase prevents the removal of acetyl groups from histones. Histones remain acetylated → DNA is less tightly coiled around histones → chromatin is more accessible to RNA polymerase. If a tumour suppressor gene had been silenced by deacetylation, its transcription can now occur. The resulting tumour suppressor protein inhibits cell division, reducing uncontrolled proliferation. [3 marks]

Summary: Regulation of Gene Expression

Key Points

MechanismKey Fact

Transcription factorsProteins; move cytoplasm → nucleus; bind regulatory DNA sequences; activate or repress transcription

OestrogenSteroid; diffuses across membrane; binds cytoplasm receptor; complex → nucleus → activates transcription

EpigeneticsHeritable changes in gene expression without changing DNA base sequence

Increased DNA methylationInhibits transcription — prevents RNA polymerase/TF binding

Decreased histone acetylationInhibits transcription — histones grip DNA more tightly

Increased acetylationStimulates transcription — DNA more accessible

RNAiPost-transcriptional; siRNA/miRNA bind complementary mRNA → mRNA degraded or translation blocked

Must-Know Language

"Heritable" — epigenetics definition requires this word

"No change to base sequence" — epigenetics definition requires this

"Cytoplasm to nucleus" — transcription factor movement

"Post-transcriptionally" — RNAi acts here, not transcription

Methylation & Acetylation Rules

↑ Methylation → ↓ transcription

↓ Methylation → ↑ transcription

↑ Acetylation → ↑ transcription

↓ Acetylation → ↓ transcription

Exam Tip

For any epigenetics question, state: (1) what the modification is, (2) how it affects chromatin structure / RNA polymerase access, (3) the effect on transcription. For the oestrogen question, state the complete pathway: membrane crossing → cytoplasm receptor → complex → nucleus → regulatory DNA → transcription. Missing any step will lose marks.