Epigenetic control of gene expression in eukaryotes. Epigenetics involves heritable changes in gene function, without changes to the base sequence of DNA. These changes are caused by changes in the environment that inhibit transcription by increased methylation of DNA or decreased acetylation of associated histones. The increased methylation of DNA and decreased acetylation of histones can inhibit transcription. Epigenetic changes can be inherited and have a role in the development of disease.

What this dot point is asking

AQA wants you to define epigenetics, explain the two named mechanisms (increased DNA methylation and decreased histone acetylation) that inhibit transcription, stress that the DNA base sequence is unchanged, and link epigenetic changes to the environment, inheritance and disease.

What epigenetics means

Epigenetic control acts on top of the genetic code. The DNA sequence is unchanged, but chemical tags attached to the DNA or to the histone proteins it wraps around determine whether a gene can be transcribed. Crucially, these tags can be influenced by the environment (for example diet, stress, toxins) and can be inherited, both as cells divide and, in some cases, between generations.

The two named mechanisms in the AQA specification both inhibit transcription.

Increased methylation of DNA

Methylation is the addition of a methyl group ($\text{CH}_3$) to a DNA base, usually to cytosine in the promoter region of a gene.

• Increased methylation inhibits transcription. The methyl groups prevent transcription factors and RNA polymerase from binding to the DNA, so the gene is not transcribed and the protein is not made.
• Methylation therefore switches genes off.

Decreased acetylation of histones

In eukaryotes, DNA is wound around histone proteins. How tightly it is wound controls whether the genes are accessible.

• Acetylation is the addition of an acetyl group to histones. Acetyl groups reduce the positive charge on the histones, so they bind the negatively charged DNA less tightly. The DNA is more loosely wound, so transcription factors and RNA polymerase can reach the gene and transcribe it.
• Decreased acetylation (removal of acetyl groups) increases the positive charge on the histones, so they bind the DNA more tightly. The DNA-histone complex becomes more condensed, transcription factors cannot bind, and transcription is inhibited.

Why epigenetic changes are heritable

When a cell divides, the methylation and acetylation pattern can be copied onto the new DNA and histones, so daughter cells inherit the same pattern of gene expression. In some organisms these tags can also escape the resetting that normally happens in gametes, so an epigenetic state acquired by a parent (for example in response to famine) can be passed to offspring. This is why epigenetics is described as heritable even though the base sequence does not change.

Role in disease

Abnormal epigenetic patterns contribute to disease, most importantly cancer:

• Hypermethylation (increased methylation) of the promoter of a tumour suppressor gene switches it off. The cell loses control of the cell cycle and can divide uncontrollably.
• Hypomethylation (decreased methylation) elsewhere can switch on genes that should be silent, such as oncogenes.

Because epigenetic changes do not alter the DNA sequence, they are potentially reversible. Drugs that block methylation or change acetylation are being developed to reactivate silenced tumour suppressor genes, an active area of cancer treatment research.

Common mistakes

Try this

Q1. Explain why decreased acetylation of histones reduces transcription. [3 marks]

• Cue. Removing acetyl groups increases the positive charge on histones, so they bind the negatively charged DNA more tightly; the DNA becomes more condensed; transcription factors and RNA polymerase cannot bind, so transcription is inhibited.

Q2. A drug reduces methylation of the promoter of a tumour suppressor gene. Suggest how this could help treat cancer. [2 marks]

• Cue. Reduced methylation allows transcription factors to bind, so the tumour suppressor gene is transcribed again; its protein restores control of the cell cycle, slowing or stopping uncontrolled cell division.

Q3. Give one piece of evidence that an observed difference in gene expression is epigenetic rather than genetic. [1 mark]

• Cue. The difference in expression occurs without any change in the DNA base sequence (for example, identical twins with the same DNA show different patterns of methylation and gene expression).