Introduction to Epigenetics

Editor's Notes

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• #4: Epigenetics is the level of control that sits above the genes and helps determine which genes are turned on and which genes are turned off. Chemical modifications to either the DNA, or structures associated with DNA, alter gene expression, without changes to the DNA sequence. The epigenome is like a chemical switch, instructing DNA/genes to be turned on or turned off. <number>
• #5: Every cell in the human body contains exactly the same DNA sequence. There is more than 2 metres of DNA inside every cell. DNA is very thin, but it still needs some compacting in order to fit inside the nucleus of each and every cell. The first step is to break the DNA up into smaller pieces, called chromosomes, and then the DNA is wound up tightly until it can all fit inside. Humans have a total of 46 chromosomes; 23 from mum and 23 from dad. <number>
• #6: Epigenetic control of which genes can be switched on and which remain off allows each cell in the human body to specialise and carry out distinctive roles. If all the cells used all genes at the same time the result would be chaos. The ability of cells to switch off some genes and switch on others allows us to have a wonderfully co-ordinated system of tissues and organs. For instance, kidney cells don’t need to use the genes that allow for extensive signalling and messaging, and brain cells don’t need to use the genes that allow for filtration of blood and production of urine. So the genes that aren’t necessary for a particular cell are switched off. <number>
• #8: If epigenetic modifications were permanent, we might as well be changing the DNA itself to gain control. Instead epigenetic modifications can change during the lifetime of a person as a result of a variety of factors. At different times in development some genes are switched on, but once their role is complete, they are switched off again. Cells are constantly responding to internal and external environmental changes. Signals can come from inside the cell, from nearby cells, or indeed from the environment. During embryonic development the signals from nearby cells are extremely important, these help determine what a cell will become. As humans age environmental signals become increasingly important in directing gene expression within cells. Environmental influences include physiological state, social group, smoker or non-smoker and whether or not you smoke - all influence epigenetic modifications. <number>
• #9: Almost as important as being able to change epigenetic signals is the ability for an embryo to be able to erase them. When an egg and a sperm get together they contain epigenetic modifications of both parents. If these were carried on into the baby all the different cells and tissue types needed for life would not be able to develop. Shortly after fertilisation, in a rapid fashion, epigenetic tags from sperm are erased. Epigentic tags from the egg are erased more slowly. When a fertilised egg is ready to implant in the uterus all epigenetic tags have been removed, and these cells can now become anything. The signals these cells receive from their neighbours helps determine what each will become. By the time the embryo has developed into a recognisable baby shape, most of the epigenetic tags needed for tissue and organ specificity have already been laid down. <number>
• #10: Any epigenetic tags or modifications that are made within a cell are carried through into the daughter cells when the cell divides. This is extremely important, as cells that have started down one functional path keep going down that path. If epigenetic tags were not passed on then each daughter cell would be able to do anything and we would not develop properly. In this diagram the cell receives a signal to develop into a nervous system cell. This message is maintained within the daughter cell, building up a cellular history. This cell may then receive signals to become a spinal cord cell, with more signals until it develops into a specialised motor neuron cell. <number>
• #11: As we get older the environment plays a more important role in determining our epigeneome. Direct influences such as diet, smoking status and other lifestyle choices all impart on epigenetic tags. Indirect things such as stress levels, friendship groups, parental relations, can also leave their mark on your epigenome. <number>
• #12: One prime example of how nutrition plays a role in the epigenome is found within bees. Queen bees and worker bees are genetically identical. Their only difference is diet; queen bees are raised on a diet of royal jelly, but worker bees are not. Royal jelly alters the genes that are switched on and off in the queen bee and she develops ovaries and a large abdomen for egg laying. She also obtains a rather queenly attitude. On the other hand, worker bees live on a diet of pollen, nectar and water and do not develop down the path of a queen bee. <number>
• #14: To understand epigenetic modifications we need to consider in detail how DNA fits inside of our cells. DNA is stored in chromosomes and then wound up tightly. Initially winding is accomplished by the natural helical shape of DNA, but more winding is required for DNA to fit inside each cell. DNA is further wound around small proteins called histones. A group of eight histones come together to form a histone octamer, and DNA is wound around the histone octamer two and a half times. These histones wind around one another repeatedly, until DNA is tightly compacted into the familiar chromosome shape. <number>
• #15: One type of epigenetic modification involves adding chemicals to the small histones that the DNA winds around. Each of the histones that make up the histone octamer (group eight histones) has a tail that protrudes from the molecule. At various points along these tails chemicals can be added or removed. Tighter winding of DNA around histone octamers, or relaxing of DNA around histone octamers, depends on which chemicals are added to histone tails, and where along the tail these chemicals are added. If DNA winds tightly around specific regions, genes are effectively hidden from the cells. In regions where DNA is unwound/loosened, the genes are exposed and are accessible by the cell. <number>
• #16: A second type of epigenetic modification works on individual genes directly, DNA methylation. Each chromosome has a number of genes that make up the instruction manual for life. Each gene carries information needed to make a particular protein, and these proteins then act within the cell, or outside of the cell, performing a specific function. For instance a gene provides the instructions to make the protein insulin, the insulin protein helps the body take up and use sugars following a meal. Each gene is made up of three main parts, instructions or RNA coding sequence, plus a promoter at the start of the gene and a terminator at the end of the gene. The promoter and terminator regions instruct the cellular machinery on where a gene begins and ends. In addition, the promoter region of a gene contains a number of different regulatory sequences to which other molecules can bind to either speed up or slow down expression of a gene. <number>
• #17: DNA methylation targets the promoter region of the genes. Promoter contain areas with a high number of C (cytosine) and G (guanine) DNA bases. The cytosine, or C, residues in these areas can have methyl groups added to them and when this occurs the genes are effectively switched off. The methyl groups basically block other proteins from binding to the promoter region and the gene sequence cannot be read. <number>
• #19: Due to the enormous influence of environment on our epigenome it can be quite hard to study and difficult to determine if environmental or genetic factors are involved in epigenetic changes. One of the best way to characterise epigenetic changes is to study traits in identical, or monozygotic twins. Monozygotic twins occur when the zygote splits into two not long after fertilisation. The DNA of the two formed embryos is identical, but the epigenomes can be vastly different. <number>
• #20: As you would expect, identical twins start out life with very similar epigenomes. They grew up in the same womb and were generally raised in the same household, and have many shared experiences. In this image researchers examined and compared the epigenetic tags of three year old twins. One twin’s methylated DNA was labelled in green, and the other with red. The twins chromosomal photos were then overlaid. Appearance of a yellow colour indicates identical methylation patterns. In some areas green or red colours are evident, these indicate small differences in methylation patterns between the identical twins. These differences could have developed due to something as simple as one twin learning to roll over earlier, or one twin receiving more nutrients in the womb. Overall at the age of three years DNA methylation patterns are virtually identical. <number>
• #21: Forty seven years later, at age fifty, and it is not the same story. In this image one twin’s methylated DNA is labelled in green and the other in red, areas of yellow indicate identical DNA methylation patterns. You can see here that the two chromosomes have diverged significantly, there are clear areas of red and clear areas of green now visible. These epigeneitc changes are due to the influence of their environment. Unless these twins spend every waking moment together, their life experiences will differ. Environmental differences may be simple, such as one twin preferring to read books while the other plays sports, or having different social groups or different jobs. But all environmental influences these twins come into contact with that differ from the other’s experience will leave a mark on their epigenome. These differences are the greatest in older twins that live apart, as their life experiences are the most varied. <number>
• #22: Many traits will be shared by identical twins, purely because they have the same genes. But other traits, which can be influenced by the environment, may differ. Looking at these traits in identical twins can tell us how much of a trait is genetically controlled and how much is affected by the environment. This graph reveals IQ scores between a range of different siblings. Identical twins raised together have more than an 85% correlation in IQ scores. If IQ was entirely controlled by genes, then we would expect a 100% correlation as both twins have the same genes. However, because there is not a 100% matching of IQ scores, there must be something else influencing IQ. <number>
• #23: Other characteristics, such as disease status, may also differ between identical twins. Due to differing environmental exposures some genes may be turned on in one twin but turned off in the other. This can mean the difference between one twin having asthma and the other not, or one twin developing cardiovascular disease and the other not. Epigenetics can play a huge role in the health of all individuals, not just twins. <number>
• #25: Why is it a good idea to find out which epigenetic tags are controlling gen expression? Epigenetic modifications do vary between individuals with and without a specific disease. If we can determine which genes are switched off that should be turned on, or vice versa, these genes can be targets for treatment. Currently it is considered easier to turn genes on or off by activating or removing epigenetic modifications than it is to change the actual DNA sequence. Therapeutic drugs which alter epigenetic tags have either already been approved for use or are under development. The biggest challenge for epigenetic therapies is to make these drugs selective, as turning off a certain gene in one cell may be advantageous, but turning it off in others may do more harm than good. <number>