Epigenetics

Epigenetics is the study of heritable changes in gene expression that do not involve changes to the underlying DNA sequence. Epigenetic mechanisms control which genes are switched on or off in a given cell, and these changes can be influenced by the environment and, in some cases, passed to future generations. This is a rapidly growing field with important implications for biology and medicine.

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What Is Epigenetics?

Key Definition: Epigenetics refers to changes in gene expression that are heritable through cell division (and sometimes across generations) without any alteration to the DNA base sequence itself.

Key principles:

• Every cell in a multicellular organism contains the same DNA, but different cell types express different genes. Epigenetic mechanisms are responsible for this differential gene expression.
• Epigenetic changes are reversible — unlike mutations, they do not permanently alter the DNA sequence.
• Epigenetic modifications regulate gene expression by altering how accessible the DNA is to the transcription machinery.
• Two main epigenetic mechanisms are studied at A-Level: DNA methylation and histone modification.

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Chromatin Structure and Gene Expression

To understand epigenetics, it is important to understand how DNA is packaged:

• DNA is wrapped around proteins called histones to form nucleosomes — the basic unit of chromatin.
• Eight histone proteins form a histone octamer, and approximately 147 base pairs of DNA are wrapped around each octamer.
• The degree of chromatin compaction affects gene expression:
  • Euchromatin — loosely packed chromatin. DNA is accessible to RNA polymerase and transcription factors. Genes in euchromatin are more likely to be actively transcribed.
  • Heterochromatin — tightly packed chromatin. DNA is less accessible. Genes in heterochromatin are generally silenced (not transcribed).

Key Definition: Chromatin is the complex of DNA and histone proteins found in the nucleus. Its structure can be modified to regulate gene expression.

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DNA Methylation

Key Definition: DNA methylation is the addition of a methyl group (–CH₃) to a cytosine base in DNA, typically at CpG sites (where a cytosine is followed by a guanine). This modification generally silences gene expression.

Mechanism

• The enzyme DNA methyltransferase catalyses the addition of a methyl group to the 5' position of cytosine, producing 5-methylcytosine.
• Methylation occurs predominantly at CpG dinucleotides (a cytosine followed by guanine, linked by a phosphodiester bond).
• Regions of DNA with a high density of CpG sites are called CpG islands and are often found in or near promoter regions.

Effects on Gene Expression

• Methylation of CpG islands in a gene's promoter region typically inhibits transcription because:
  • Methyl groups can directly block the binding of transcription factors to the promoter.
  • Methylated DNA recruits methyl-CpG-binding proteins, which in turn recruit histone-modifying enzymes that compact the chromatin.
• Methylation within the gene body (the transcribed region) can sometimes be associated with active transcription — the relationship is complex.
• DNA methylation patterns are maintained through cell division by the enzyme maintenance methyltransferase, which recognises hemi-methylated DNA (where one strand is methylated and the newly synthesised strand is not) and methylates the new strand.

Examples

• X-chromosome inactivation: In female mammals, one of the two X chromosomes is extensively methylated and condensed into a Barr body. Most genes on the inactivated X chromosome are silenced. This is a form of dosage compensation, ensuring that females (XX) do not produce twice as much X-linked gene product as males (XY).
• Genomic imprinting: Certain genes are expressed from only one parental allele (either the maternal or paternal copy), with the other copy being silenced by methylation. An example is the IGF2 gene (insulin-like growth factor 2), which is expressed only from the paternal allele.
• Cancer: Abnormal methylation patterns are a hallmark of many cancers. Hypermethylation of tumour suppressor gene promoters can silence these genes, contributing to uncontrolled cell division. Conversely, hypomethylation of oncogene promoters can increase their expression.

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Histone Modification

Key Definition: Histone modification refers to the addition or removal of chemical groups to the amino acid tails of histone proteins, which alters chromatin structure and thereby regulates gene expression.

Histone Acetylation