Epigenetic control of gene expression

• gene expression is not just controlled by transcription factors

  epigenetic changes also play a part in whether a gene is expressed or not
• how does epigenetic control work?

  • in eukaryotes, epigenetic control can determine whether a gene is switched on or off i.e. whether the gene is expressed (transcribed and translated) or not
  • it works through the attachment of removal of chemical groups - epigenetic marks to or from DNA or histone proteins
• • epigenetic marks do not alter the base sequence of DNA
  • instead, they alter how easy it is for the enzymes and other proteins needed for transcription to interact with and transcribe the DNA
  • epigenetic changes to gene expression play a role in lots of normal cellular processes and can also occur in response to changes in the environment - e.g. pollution and availability of food
• Inheriting epigenetic changes:

  • organisms inherit their DNA base sequence from parents
  • most epigenetic marks on the DNA are removed between generations, some escape the removal process and are passed on to offspring
  • this means that the expression of some genes in the offspring can be affected by environmental changes that affected their parents or grandparents
• e.g. epigenetic changes in some plants in response to drought have been shown to be passed on to later generations
• epigenetic marks are important for cell specialisation:

  • most epigenetic marks are removed between generations bc cells from the fertilised egg need to be able to become any type of cell - need to be totipotent
• there are several epigenetic mechanisms used to control gene expression:

  • methylation of DNA
  • acetylation of histones
• increased methylation of DNA:

  • methylation is when a methyl group (an example of an epigenetic mark) is attached to the DNA coding for a gene
  • the group always attaches at a CpG site, which is where a cytosine and guanine base are next to each other in the DNA (linked by a phosphodiester bond)
  • increased methylation changes the DNA structure so that the transcriptional machinery (enzymes etc) can't interact with the gene - so the gene is not expressed i.e. it is switched off
• decreased acetylation of histones:

  • histones are proteins that DNA wraps around to form chromatin, which makes up chromosomes
  • chromatin can be highly condensed or less condensed
  • how condensed it is affects the accessibility of the DNA and whether or not it can be transcribed
  • histones can be epigenetically modified by the addition or removal of acetyl groups (another example of an epigenetic mark)
• • when histones are acetylated, the chromatin is less condensed
  • this means that the transcriptional machinery can access the DNA, allowing genes to be transcribed
  • when acetyl groups are removed from the histones, the chromatin becomes highly condensed and genes in the DNA can't be transcribed bc the transcriptional machinery can't physically access them
  • histone deacetylase (HDAC) enzymes are responsible for removing the acetyl groups
• the methyl group is attached to cytosine by enzymes called methyltransferases
• acetyl group = -COCH3 group
• development of disease:

  • e.g. abnormal methylation of tumour suppressor genes and oncogenes can cause cancer
  • Fragile-X syndrome
  • Angelman syndrome
  • Prader-Willi syndrome
• Fragile-X syndrome


  A genetic disorder that can cause symptoms such as learning and behavioural difficulties, as well as characteristic physical features
• Fragile-X syndrome mutation


  1. The mutation results in the short DNA sequence CGG being repeated many more times than it should

  2. More CpG sites result in increased methylation of the gene, which switches it off

  3. The lack of the protein that the gene codes for causes the symptoms of the disease
• More CpG sites in the gene than usual - results in increased methylation of the gene - switches it off
• The gene is switched off, so the protein it codes for isn't produced - the lack of this protein that causes symptoms
• Angelman syndrome:

  • genetic disorder that affects the nervous system and causes symptoms such as delayed development and motor problems
  • caused by a mutation of deletion of a region of chromosome 15
  • in most cases - maternal allele in the affected region of chromosome 15 is missing
  • paternal allele present in the cell but is is switched off by methylation - so gene is not transcribed
  • like for fragile-X syndrome this means that a protein is not produced - leads to symptoms
• the FMR1 CGG sequence is normally repeated between 5 and 40 times, but in the mutated gene it's repeated over 200 x
• Prader-Willi syndrome:

  • genetic disorder characterised by developmental issues and excessive hunger
  • most cases are caused by the loss of function of genes from the same region of chromosome 15 as Angelman syndrome
  • however, in this case it is the paternal allele that's usually transcribed and so the syndrome results when the deletion occurs on the paternal chromosome
  • the maternal gene is silenced by methylation and so is unable to compensate
  • lack of protein encoded by this gene leads to the disorder
• epigenetic changes are a lot easier to treat than DNA sequence mutations (due to their reversibility)
• Treating disease:

  • epigenetic changes are reversible, which makes them good targets for new drugs to combat the disease they cause
  • these drugs are designed to counteract the epigenetic changes that cause the diseases
  • e.g. increased methylation is an epigenetic change that can lead to a gene being switched off
  • drugs that stop DNA methylation can sometimes be used to treat diseases caused in this way
• For example:

  • the drug azacitidine is used in chemotherapy for types of cancer that are caused by increased methylation of tumour suppressor genes
  • tumour suppressor genes usually slow cell division, so if they are switched off be methylation, cells asre able to divide uncontrollably can can form a tumour
  • azacitidine inhibits the methylation of these genes by physically blocking the enzmes involved in the process
• • decreased acetylation can also lead to genes being switched off
  • HDAC inhibitor drugs e.g. romidepsin, can be used to treat diseases that are caused in this way - including some types of cancer
  • these drugs work by inhibiting the activity of histone deactylase (HDAC) enzymes, which are responsible for removing acetyl groups from the histones
  • without the activity of HDAC enzymes, the genes remain acetylated and the proteins they code for can be transcribed
• • the problem with developing drugs to counteract epigenetic changes is that these changes take place normally in a lot of cells
  • important to make sure the drugs are as specific as possible
  • e.g. drugs used in cancer therapies can be designed to only target dividing cells to avoid damaging normal body cells
• if these drugs that counteract epigenetic changes also activate transcription in normal cells, the cells could become cancerous creating the very problem that the drugs are supposed to treat