3.8.2.2 Regulation of Transcription and Translation
What do we need to know from the specification?
1. Explain how transcription factors stimulate / inhibit transcription
2. Explain how oestrogen affects gene transcription
3.i State what is meant by epigenetics
The definition for epigenetics is
"the study of changes in organisms caused by modification of gene expression by environmental factors rather than alteration of the genetic code itself.", however if asked to state the definition in an exam, make sure to incorporate some of the following:
Epigenetics is a relatively new field in biology, which explores how environmental factors such as toxins, diet, exercise cans subtly alter the genetic inheritance of the organisms offspring. It is also the exploration as to how these influences can cause diseases such as autism and cancer.
3.ii Describe the nature of the epigenome
We know from GCSE that DNA is wrapped around proteins called histones, which together form the DNA-histone complex, called a chromatin. Relatively recent scientific research has discovered that both the DNA and the histones are covered in chemical 'tags'. These tags form a second layer to genetic coding, and together they are called the epigenome. It is the genome which determines the shape of the chromatin. Through its determination of the shape of the chromatin, the epigenome has the ability to determine which genes can and cannot be expressed. The shape of the epigenome is determined by all the chemical signals it has received in its lifetime, therefore acts as a cellular memory.
We learnt above that in order for a gene to be transcribed, it needs to have a transcription factor attached to it, however sometimes the epigenome will make the gene inaccessible for the transcription factor. It does this by coiling the gene tightly around the histones so that it is very compact and the transcription factor cannot reach it.In this way, the gene can be described as being 'switched off'. By contrast, genes which are 'switched on' are not coiled tightly around the histones and so are accessible for the transcription factors.
The chromatin has two states it can be in;
4. Describe and explain the link between heredity and epigenetics
It used to be believed that a new born embryo had has all of its epigenome erased through a process of reprogramming, which happens in the sperm and eggs in order to create a 'clean' genome. However recent discoveries show this process of reprogramming doesn't erase all of the tags that make up the epigenome. In fact about 1% of genes escape the process of genetic reprogramming by a process called imprinting (beyond spec.)
An example of epigenetic inheritance is the inheritance of the condition gestational diabeties. If a pregnant mother has the condition, the fetus is exposed to very high levels of glucose, which cause epigenetic changes in the offsprings DNA, and increase the likelihood of the offspring developing gestational diabetes.
Acetylation is the process by which an acetyl group is added to a molecule. When the histones are receiving acetyl groups, it is from the donor molecule Acetylcoenzyme A. Deacetylation is the reverse of the process. Acetyl groups have a negative charge, therefore there is natural repulsion between the acetyl groups and the DNA's phosphate groups (which also have a negative charge). If the levels of acetylation on the associated histones were to be decreased, then the charges on the histones would increase which would lead to greater attraction between the histones and the DNA and so more, tighter coiling. Therefore, in the region in which decreased acetylation occurs, the genes would be switched off, as transcription factors would be unable to access the gene. Therefroe decreasing acetylation is an inhibitory action.
If acetylation were to be increased, then there would be a decrease in charge on the histones, and so greater repulsion between the histones and the DNA, and so looser, less condense coiling. This would allow any genes in this region to be accessible to the transcription factors. Therefore the gene would be switched on. Increasing acetylation is an exhibitory action.
5.3 Explain the effects of increased methylation of DNA
Methylation is the process of adding a CH3 group to a molecule. In this context, the molecule receiving the CH3 group is the DNA base cytosine. The methylation of DNA in this way, inhibits the transcription of DNA in two different ways:
6. Explain the relevance of epigenetics on the development, diagnosis and treatment of diseases such as cancer
While some epigenetic changes are normal for healthy development, some are responsible for diseases, such as cancer. Any alteration of the genetic processes can cause the unwanted expression / silencing of certain genes.
In 1983, researchers discovered that tissue taken from patients suffering from colorectal cancer had a lower level of methylation in their diseased tissue than their normal tissue. As increased methylation of DNA causes gene inhibition, those with lower levels of DNA inhibition therefore exhibited higher levels of gene activity than normal.
Cancer- in DNA, there is a region near the promoter region which has no methylation, in order to ensure gene expression. In cancer cells however, this region becomes methylated and so switches genes which should be active to off. This happens early on in the development of cancer. Epigenetic changes don't cause changes in base sequence, but can cause changes in the frequency of mutation. There exists certain genes which should remain on, which produce proteins whose purpose is to repair DNA which has mutated. It has been discovered that very early on in the development of cancer, there is increased methylation of these genes, meaning they are not expressed and so these protective genes are switched off, and mutated genes are free to develop into cancer.
Diseases such as cancer are caused by epigenetic changed which activate or silence a gene. Therefore treatments have been developed to try and counteract the initial epigenetic changes. These treatments use drugs which inhibit certain enzymes involved in either histone acetylation or DNA methylation.
E.g. A drug which inhibits enzymes which cause DNA methylation would act to reactivate a silenced gene.
It is important that epigenetic treatments only affect the affected cells, otherwise they could activate or silence genes unnecessarily, which could actually cause cancer.
Epigenetics can also be used in the diagnosis of diseases such as autism, arthiritis and cancer, by testing levels of methylation/acetylation in the potentially diseased tissue. Early diagnosis will allow a better chance of cure.
7.i State what small interfering RNA (siRNA) is
Small interfering RNA (siRNA) is a small double stranded molecule of RNA responsible for breaking up strands of mRNA before they can be translated into a polypeptide.
7.ii Explain how siRNA affects gene expression
Summary Questions
1. Explain what is meant by epigenetics
Epigenetics is the process by which environmental factors can cause heritable changes in gene function without changing the base sequence of DNA.
2. Name two mechanisms by which changes in the environment can inhibit transcription
Students should be able to evaluate the appropriate data for the relative influences of genetic and environmental factors on phenotype.
1. Environmental
2. If the influence were totally genetic, then the plants which were genetically identical would show the same phenotype regardless of where they were grown. The greater the environmental influence, the greater the differences in phenotype between the genetically identical plants. As there are major differences in phenotype for the genetically identical plants, the main factor must be environmental.
3.Environmental conditions at higher altitudes are more extreme than those at lower altitudes, and less suited for photosynthesis (colder, windier, less soil). Plants from high altitudes have adapted to survive in these extremes, therefore the conditions at lower altitudes prevent fewer problems and they thrive. Plants that have evolved at low altitude, by contrast, find harsher conditions at higher altitudes and struggle to grow.
3.i State what is meant by epigenetics
3.ii Describe the nature of the epigenome
3.ii Describe the nature of the epigenome
4. Describe and explain the link between heredity and epigenetics
5.1 Explain how environmental factors are detected by the epigenome
5.2 Explain the effects of decreased acetylation of histones
5.3 Explain the effects of increased methylation of DNA
6. Explain the relevance of epigenetics on the development, diagnosis and treatment of diseases such as cancer
7.i State what small interfering RNA (siRNA) is
7.ii Explain how siRNA affects gene expression
1. Explain how transcription factors stimulate / inhibit transcription
In multi-cellular organisms, each cell is specialised to perform a certain type of role. For example, Beta cells in the pancreas are specialised to produce the hormone insulin. Insulin is a protein and therefore, the production of insulin requires the transcription of the gene coding for the polypeptides which make up insulin into mRNA. All cells are genetically identical, which means that (e.g.) a muscle cell also contains the gene for insulin in its DNA. However as insulin is produced only in the Beta cells, not the muscle cells, there must be some process by which the expression of a gene is controlled. This process is the Regulation of transcription and translation and involves the use of molecules such called transcription factors.
A transcription factor is a molecule which stimulates the transcription of a gene.
The transcription factor is shown to the left and is comrpised of two many parts The part in left is responsible for binding to DNA ans the part on the right is responsible for activating the transcription factor.. It is found in the cytoplasm of a cell, and needs to be activated before it can induce transcription. The transcription factor has a receptor site (on the blue part) to which another specific molecule e.g. oestrogen can bind to. Once this binding occurs, a change in the tertiary structure is caused in the part responsible for DNA binding (LHS). This change makes the DNA binding site complementary to a specific sequence of base pairs in the DNA and so the transcription factor moves into the nucleus through a nuclear pore to bind with a specific section of DNA and from there induces the process of transcription.
- The transcription factor is described as active only if it has bound to the molecule on the RHS in the image. If this binding doesn't occur, the transcription factor is inactive and the DNA binding site will not change shape to be complementary to the requires section of DNA. Therefore when inactive, the transcription factor will not cause transcription and protein synthesis.
2. Explain how oestrogen affects gene transcription
Oestrogen itself is not a transcription factor, however is the molecule which binds to a transcription factor in order to activate it. Therefore oestrogen can be described as an activator molecule. It is a lipid hormone. Oestrogen is produced in women in the ovaries, however it has effects all over the body. Oestrogen is therefore carried in the blood to its target cells. As it's a lipid molecule, it therefore is lipid soluble so can move across the cell's surface membrane. Oestrogen then binds with the transcription factor as shows in image above. This activates the transcriptions factor and it is now able to enter the nucleus via a nuclear pore. Inside the nucleus, the transcription factor binds to specific DNA base pair sequences on the DNA molecule. The binding of the transcription factor to the DNA stimulates transcription of the gene. The process is demonstrated below.
The definition for epigenetics is
"the study of changes in organisms caused by modification of gene expression by environmental factors rather than alteration of the genetic code itself.", however if asked to state the definition in an exam, make sure to incorporate some of the following:
Epigenetics is a relatively new field in biology, which explores how environmental factors such as toxins, diet, exercise cans subtly alter the genetic inheritance of the organisms offspring. It is also the exploration as to how these influences can cause diseases such as autism and cancer.
3.ii Describe the nature of the epigenome
We know from GCSE that DNA is wrapped around proteins called histones, which together form the DNA-histone complex, called a chromatin. Relatively recent scientific research has discovered that both the DNA and the histones are covered in chemical 'tags'. These tags form a second layer to genetic coding, and together they are called the epigenome. It is the genome which determines the shape of the chromatin. Through its determination of the shape of the chromatin, the epigenome has the ability to determine which genes can and cannot be expressed. The shape of the epigenome is determined by all the chemical signals it has received in its lifetime, therefore acts as a cellular memory.
We learnt above that in order for a gene to be transcribed, it needs to have a transcription factor attached to it, however sometimes the epigenome will make the gene inaccessible for the transcription factor. It does this by coiling the gene tightly around the histones so that it is very compact and the transcription factor cannot reach it.In this way, the gene can be described as being 'switched off'. By contrast, genes which are 'switched on' are not coiled tightly around the histones and so are accessible for the transcription factors.
The chromatin has two states it can be in;
- Heterochromatin; which is shown on the left of the above image. This is when the DNA is wrapped tightly around the histones, creating a very condense chromatin. In this state, a gene is inaccessible for a transcription factor.
- Euchromatin; which is shown on the right of the above image. This is when the DNA is wrapped loosely around the histones, creating a not very condense chromatin. In this state, a gene is accessible for a transcription factor.
4. Describe and explain the link between heredity and epigenetics
It used to be believed that a new born embryo had has all of its epigenome erased through a process of reprogramming, which happens in the sperm and eggs in order to create a 'clean' genome. However recent discoveries show this process of reprogramming doesn't erase all of the tags that make up the epigenome. In fact about 1% of genes escape the process of genetic reprogramming by a process called imprinting (beyond spec.)
An example of epigenetic inheritance is the inheritance of the condition gestational diabeties. If a pregnant mother has the condition, the fetus is exposed to very high levels of glucose, which cause epigenetic changes in the offsprings DNA, and increase the likelihood of the offspring developing gestational diabetes.
5.1 Explain how environmental factors are detected by the epigenome
Every kind of environmental factor (signal) which can influence the epigenome will have a specific 'message'. The signal will stimulate proteins to transport its message across the cell membrane into the cell, where it is passed via a series of other proteins through the cell's cytoplasm into the nucleus where it binds to a specific protein. This specific protein attaches to a specific sequence of bases in the DNA. Once attached the protein can have two effects:
- It can affect the levels of acetylation of the associated histones
- It can affect the levels of methylation of the DNA
5.2 Explain the effects of decreased acetylation of histones
If acetylation were to be increased, then there would be a decrease in charge on the histones, and so greater repulsion between the histones and the DNA, and so looser, less condense coiling. This would allow any genes in this region to be accessible to the transcription factors. Therefore the gene would be switched on. Increasing acetylation is an exhibitory action.
5.3 Explain the effects of increased methylation of DNA
Methylation is the process of adding a CH3 group to a molecule. In this context, the molecule receiving the CH3 group is the DNA base cytosine. The methylation of DNA in this way, inhibits the transcription of DNA in two different ways:
- With the CH3 group bound to the cytosine, no transcriptional factors are able to access the cytosine and therefore no transcription can occur.
- The methyl group attracts proteins which condense the chromatin by inducing the deacetylation of histones
6. Explain the relevance of epigenetics on the development, diagnosis and treatment of diseases such as cancer
While some epigenetic changes are normal for healthy development, some are responsible for diseases, such as cancer. Any alteration of the genetic processes can cause the unwanted expression / silencing of certain genes.
In 1983, researchers discovered that tissue taken from patients suffering from colorectal cancer had a lower level of methylation in their diseased tissue than their normal tissue. As increased methylation of DNA causes gene inhibition, those with lower levels of DNA inhibition therefore exhibited higher levels of gene activity than normal.
Cancer- in DNA, there is a region near the promoter region which has no methylation, in order to ensure gene expression. In cancer cells however, this region becomes methylated and so switches genes which should be active to off. This happens early on in the development of cancer. Epigenetic changes don't cause changes in base sequence, but can cause changes in the frequency of mutation. There exists certain genes which should remain on, which produce proteins whose purpose is to repair DNA which has mutated. It has been discovered that very early on in the development of cancer, there is increased methylation of these genes, meaning they are not expressed and so these protective genes are switched off, and mutated genes are free to develop into cancer.
Diseases such as cancer are caused by epigenetic changed which activate or silence a gene. Therefore treatments have been developed to try and counteract the initial epigenetic changes. These treatments use drugs which inhibit certain enzymes involved in either histone acetylation or DNA methylation.
E.g. A drug which inhibits enzymes which cause DNA methylation would act to reactivate a silenced gene.
It is important that epigenetic treatments only affect the affected cells, otherwise they could activate or silence genes unnecessarily, which could actually cause cancer.
Epigenetics can also be used in the diagnosis of diseases such as autism, arthiritis and cancer, by testing levels of methylation/acetylation in the potentially diseased tissue. Early diagnosis will allow a better chance of cure.
7.i State what small interfering RNA (siRNA) is
Small interfering RNA (siRNA) is a small double stranded molecule of RNA responsible for breaking up strands of mRNA before they can be translated into a polypeptide.
7.ii Explain how siRNA affects gene expression
- An enzyme cuts down large double stranded molecules of RNA into smaller sections called small interfering RNA.
- One of the two siRNA strands combines with an enzyme.
- The siRNA molecule guides the enzyme to a messenger RNA molecule by pairing up its bases with the complementary ones on a section of the mRNA molecule.
- Once in position, the enzyme cuts the mRNA molecule into smaller sections.
- The mRNA is no longer capable of being translated into a polypeptide
- Therefore the gene hasn't been expressed, i.e. it is blocked.
Summary Questions
1. Explain what is meant by epigenetics
Epigenetics is the process by which environmental factors can cause heritable changes in gene function without changing the base sequence of DNA.
2. Name two mechanisms by which changes in the environment can inhibit transcription
- Decreased histone acetylation
- Increased DNA methylation
3. One of the two strands of siRNA combines with an enzyme and guides it to a mRNA molecule which it then cuts. Explain why the mRNA is unlikely to be cut if the other strand of siRNA combines with the enzyme
The other strand would have complementary bases (i.e. GCUA instead of CGUA respectively). It is unlikely that these opposite base pairings would complement a sequence on the mRNA. The siRNA, with enzyme attached, would therefore not bind to the mRNA and so would be unaffected.
4. Suggest how siRNA could be used to:
a) identify the role of genes in a biological pathway
b) to prevent certain diseases
a) Some siRNA that blocks a particular gene could be added to cells. By observing the effects (or lack of) we could determine what the role of the blocked gene is.
b) siRNA could be used to prevent the disease by blocking the gene that causes it.
5. The enzyme histone deacetylase (HDAC) removes acetyl groups from histones. Suggest what the effect of this enzyme would be on:
a) the arrangement of chromatin (DNA-histone complex)
b) transcription
a) The chromatin would be more closely condesnsed, it would be heterochromatin.
b) Transcription would cease
Students should be able to interpret data provided from investigations into gene expression
1. The advantage of fetal haemoglobin having a greater affinity for oxygen is that it can load oxygen efficiently from the mother at the placenta where the two supplies come close together.
2. At birth, there is 20% beta globulin, 30% gamma globulin and 50% alpha globulin
3. At 30 weeks, the expression of alpha globulin remains constant, however gene for gamma globulin is expressed less, and the gene for beta globulin is expressed more.
4. After 30 weeks, there is a decrease in the expression of the gene for gamma globulin. This could be due to the gene being blocked due to the mRNA being broken down by siRNA, or the prevention of transcription due to increased methylation of DNA or decreased acetylation of histones.
5. A possible therapy would be to express the gene for gamma globulin and to inhibit the gene for beta globulin. This would result in the haemoglobin produced being similar to that of fetal, and so reduced symptoms of sickle cell disease.
Students should be able to evaluate the appropriate data for the relative influences of genetic and environmental factors on phenotype.
1. Environmental
2. If the influence were totally genetic, then the plants which were genetically identical would show the same phenotype regardless of where they were grown. The greater the environmental influence, the greater the differences in phenotype between the genetically identical plants. As there are major differences in phenotype for the genetically identical plants, the main factor must be environmental.
3.Environmental conditions at higher altitudes are more extreme than those at lower altitudes, and less suited for photosynthesis (colder, windier, less soil). Plants from high altitudes have adapted to survive in these extremes, therefore the conditions at lower altitudes prevent fewer problems and they thrive. Plants that have evolved at low altitude, by contrast, find harsher conditions at higher altitudes and struggle to grow.
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