| Epigenetic control of gene expression | Ever since James Watson and Francis Crick proposed the double-helix model in 1953, it has been taken as fact that DNA possesses the instructions for making all parts of an organism. In recent years, however, we have come to realise that DNA is only part of the story of heredity. It is accepted that while genes determine the features of an organism, the environment can influence the expression of these genes (Topic 18.2). However, the changes they cause to the phencrype were thought not to be inherited by the offspring. We now believe that environmental factors can cause heritable changes in gene function without changing the base sequence of DNA. This process is known as epigenetics. |
| Epigenetics | spigenetics is a relatively new scientific field that provides explanations as to how environmental influences such as diet, stress, toxins, etc. can subtly alter the genetic inheritance of an organism's ofispring. It IS helping to explain, and maybe cure, illnesses ranging from diabetes
10 Cancer. It is even causing scientists to look again at previously discredited theories of evolution that suggested characteristics acquired during an organism's life could be passed on to future generatons
(Lamarckism). |
| The epigenome | We learned in Topic 8.2 that DNA is wrapped around proteins called histones. We now know that both the DNA and histones are covered in chemicals, sometimes called tags. These chemical tags form a second layer known as the epigenome. The epigenome determines the shape of the DNA-histone complex. For example it keeps genes that are inactive in a tightly packed arrangement and therefore ensures that they cannot be read (it keeps them switched off). This is known as epigenetic silencing. By contrast, it unwraps active genes so that the DNA is exposed and can easily be transcribed (switches them on).
We know that the DNA code is fixed. The epigenome, however, is flexible. This is because its chemical tags respond to environmental changes. Factors like diet and stress can cause the chemical tags to adjust the wrapping and unwrapping of the DNA and so switch genes on and off.
the epigenome of a cell is the accumulation of the signals it has deceived during its lifetime and it therefore acts like a cellular memory. In early development, the signals come from within the cells of the fetus and the nutrition provided by the mother
15 Important in shaping the epigenome at this stage. After birth, and throughout life, environmental factors affect the epigenome, athough signals from within the body, for example, hormones, also influence it. These factors cause the epigenome to activate or inhibit specific sets of the environmental signal stimulates proteins to carry its message inside the cell from where it is passed by a series of other proteins into the nucleus. Here the message passes to a specific protein which can be attached to a specific sequence of bases on the DNA. Once attached the protein has two possible elects. |
| It can change: | • acetylation of histones leading to the activation or inhibition a gene
• methylation of DNA by attracting enzymes that can add or remove methyl groups. |
| The DNA-histone complex (chromatin) | Where the association of histones with DNA is weak, the DNA-histone complex is less condensed (loosely packed). In this condition the DNA is accessible by transcription factors, which can initiate production of mRNA, that is, can switch the gene on.
Where this association is stronger, the DNA-histone complex is more condensed (tightly packed). In this condition the DNA is not accessible by transcription factors, which therefore cannot initiate production of mRNA, that is, the gene is switched off.
Condensation of the DNA-histone complex therefore inhibits transcription. It can be brought about by decreased acetylation of the histones or by methylation of DNA. Let us turn our attention to these two processes and how they inhibit transcription. |
| Decreased acetylation of associated histones | Acetylation is the process whereby an acety! group is transterred to a molecule. In this case the group donating the acety, group is acety coenzyme A which you may remember from the link reaction in respiration (Topic 12.2). Deacetylation is the reverse reaction where an acetyl group is removed from a molecule.
Decreased acetylation increases the positive charges on histones and therefore increases their attraction to the phosphate groups of DNA.
The association between DNA and histones is stronger and the DNA is not accessible to transcription factors. These transcription factors cannot initiate mRNA production from DNA. In other words, the gene is switched off. |
| Increased methylation of DNA | Methylation is the addition of a methyl group (CHy) to a molecule.
In this case the methyl group is added to the cytosine bases of DNA.
Methylation normally inhibits the transcription of genes in two ways.
o preventing the binding of transcriptional factors to the DNA
o attracting proteins that condense the DNA-histone complex (by inducing deacetylation of the histones) making the DNA inaccessible to transcription factors. |
| Epigenetics and inheritance | Unexpected though it might be, there is now little doubt that epigenetic inheritance takes place. Experiments on rats have shown that female offspring who received good care when young, respond better to stress in later life and themselves nurture their offspring better. Female offspring receiving low-quality care, nurture their offspring less well. Good maternal behaviour in rats transmits epigenetic information onto their offspring's DNA without passing through an egg or sperm.
In humans, when a mother has a condition known as gestational diabetes, the fetus is exposed to high concentrations of glucose.
These high glucose concentrations cause epigenetic changes in the daughter's DNA, increasing the likelihood that she will develop gestational diabetes herselt.
It is thought that in sperm and eggs during the earliest stages of development a specialised cellular mechanism searches the genome and erases its epigenetic tags in order to return the cells to a genetic
'clean slate'. However, a few epigenetic tags escape this process and pass unchanged from parent to offspring. |
| Epigenetics and disease | Epigenetic changes are part of normal development and health but they can also be responsible for certain diseases. Altering any of the epigenetic processes can cause abnormal activation or silencing Of genes. Such alterations have been associated with a number of diseases including cancer. In some cases the activation of a normally inactive gene can cause cancer, in other cases it is the inactivation of a tormally active gene that gives rise to the disease. In 1983, researchers found that diseased tissue taken from patients With colorectal cancer had less DNA methylation than normal tissue from the same patients. As we saw earler, increased DNA methylation normally inhibits transcription (switches off genes). This means that these patients with less DNA methylation would have higher than normal gene activity - more genes were turned on.
It is known that there are specific sections of DNA (ones near regions called promoter regions) that have no methylation in normal cells. However, in cancer cells these regions become highly methylated causing genes that should be active to switch oft. This abnormality happens early in the development of cancer.
We have seen that epigenetic changes do not alter the sequence of bases in DNA. They can, however, increase the incidence of mutations.
Some active genes normally help repair DNA and so prevent cancers.
In people with various types of inherited cancer, it is found that increased methylation of these genes has led to these protective genes being switched off. As a result, damaged base sequences in DNA are not repaired and so can lead to cancer. |
| Treating diseases with epigenetic therapy | As we have seen, many diseases, such as cancer, are triggered by epigenetic changes that cause certain genes to be activated or silenced. It is therefore logical to try to use epigenetic treatments to counteract these changes. These treatments use drugs to inhibit certain enzymes involved in either histone acetylation or DNA methylation. For example, drugs that inhibit enzymes that cause DNA methylation can reactivate genes that have been silenced.
Epigenetic therapy must be specifically targeted on cancer cells.
If the drugs were to affect normal cells they could activate gene transcription and make them cancerous, so causing the very disorder they were designed to cure.
Another use of epigenetics in disease treatment has been the development of diagnostic tests that help to detect the early stages of diseases such as cancer, brain disorders and arthritis. These tests call identily the level of DNA methylation and histone acetylation at al early stage of disease. This allows those with these diseases to seek early treatment and so have a better chance of cure. |
| EPIGENETICS ‘on top of genetics’ | - Heritable changes in gene function without changes in DNA base sequence
- This is the idea that ‘markers’ can be placed on DNA, which will affect gene expression |
| Genome | - All the genes that make an organism |
| Epigenome | - The chemical ‘tags’ that attach to DNA or Histones |
| How do nucleosomes regulate gene expression ? | - When DNA is wrapped around histones it can not be transcribed because transcription factors can not bind (gene switched off)
- Histones are positive so attract negatively charged DNA
- If the amino acids are modified and the charges neutralised the nucleosomes unravel allowing transcription (gene switched on) |
| Acetylation | - Adding an acetyl group
(neutralises charge on the amino acid lysine so DNA is less attracted)
- Removes a bond between the histone + DNA, DNA less tightly wrapped
- So transcription factors, therefore RNA pol., can more easily bind so gene expression is stimulated |
| Deacetylation | - Removing acetyl makes histones more positive
- So they attract DNA (negative)
- Removal of acetyl (deacetylation) returns lysine to its positively charged state which has a stronger attraction to the DNA molecule and therefore inhibits transcription |
| Methylation | - Adding of methyl group
- Binds to cytosine base
- Changes its shape - transcription factor can't bind |
