So, epigenetic control isn't just important in the differentiation of the three cell types we spoke about in the last lecture, but in fact, it's important throughout development. And this is consistent with the idea that I mentioned that epigenetic marks demarcate the beginnings and the ends of chromosomes and the middle of chromosomes. So, because epigenetic control is important in chromosome structure, as well as in the control of gene expression, of course, that's important for every cell type. So, here I'm showing you in this diagram that epigenetic control is important throughout development, from the single cell fertilised egg, or otherwise known as the zygote. Through pre-implantation development. So, this is before the embryo has actually implanted into the uterus to make a placenta. Post implantation development, this strange looking embryo here, through mid gestation development. The development of many different cell types in the adult. For example here, showing the blood cell system. and even through to the generation of the sperm and the eggs. Particular epigenetic marks are very important in this case, because these highly specialised structures, the sperm and the egg require a unique set of epigenetic marks to be able to allow their particular functions. So, these epigenetic marks are laid down throughout development and this helps to ensure, to specify cellular identity, and for that cellular identity to be maintained. But in addition, these marks need to be removed between development. And that's why there's this break in the arrow here, to indicate that they're removed between generations to ensure totipotency for the next generation. So, as you might expect then for this ubiquitously important process of epigenetic control. When it goes wrong, it results in a wide array of different disorders and some of these we'll cover in later lectures. For example, the imprinting disorders, and these result of epigenetic control goes wrong in either the gametes or in early development. Abhorrent epigenetic control can result in early embryonic lethality, slightly later early embryonic lethality if the placenta fails, and it can result in many different types of tumours. So for example, germ cell tumours, so these are the ones for example, found in the ovary, where an oocyte will generate a tumour. And because of its ability to be able to make many different cell types when fertilised by a sperm, a tumour derived from these cells can actually have many different cell types in there as well. And tumour genesis in the adult of many different kinds, so for example leukaemia is found in the blood system, skin cancer, breast cancer, colon cancer, any cancer that you can think of has epigenetic abnormalities. And we're going to spend some time thinking about this in later lectures. Abhorrent epigenetic control or epigenetic mistakes are also found and result in blocks of differentiation. What I mean here is that, a cell that is a precursor cell for example, of a B cell may not be able to actually make a mature B cell, cannot continue to progress through to make a mature B cell And instead, gets stuck at a earlier stage, if there are some epigenetic abnormalities. And finally, if you don't have appropriate epigenetic control in the egg and the sperm, this results in infertility. So, in each of these cases we're talking about, throughout development, we're talking about cells that have identical genetic information and yet they have different cellular makeups. But if you think about it we also know this doesn't just happen with genetically identical cells within one person but we know that there are examples of genetically identical people. So that is identical twins, monozygotic twins. What's interesting about monozygotic twins is sometimes they actually display, they look a little different so they're a bit discordant for their phenotype or their phenotypic makeup but on some occasions they're even discordant for disease. So this is really the same situation but instead of being a cell by cell basis now, it's instead the difference between individuals. So just to remind you, the way that identical twins are made. It's you have a single egg and a single sperm undergo fertilisation. This embryo, zygote, this single cell fertilised egg here will then divide to make a two cell embryo. And at the two-cell stage or later, it splits to make two separate embryos. But because they derived from the same sperm and the same egg, they are absolutely genetically identical. So what's interesting in this light is that identical twins can sometimes have different appearances. So these two twin little boys that you're seeing here don't really have different appearances. They look very similar. But we actually know if you take any particular phenotypic trait, and you measure it, say for example, height, which is obviously a nice quantitative trait, then about 30% of twin pairs will be different in their measure of height. The same is true if you look at almost any other trait that you can measure and indeed, it's also true for disease. So sometimes you'll find that there'll be a twin pair that both carry a disease gene but only one of them is afflicted. So this is a very interesting scenario. And, and what we really want to ask is, well, why can this occur, and how does it occur. Because if we can work out how it happens in the first place perhaps we can learn how to treat the disorder. Perhaps we can work out why one of those twins is is healthy despite them carrying that disease gene. So what's become clear in the recent years is that perhaps this is because sometimes these genetically identical twins are epigenetically different. And again this is something we'll deal with in the later slides. So it's now time to think about how we can define epigenetics. I told you about when it was first used and it was used with this prefix ‘epi’ just to be able to say that there was additional information in addition to the genetic information. So, Conrad Waddington was one of the first people to use this term back in the 1940s. And he said that the study of epigenesis was really thinking about how the genotypes can give rise to the phenotypes during development. And this is what we've already mentioned, essentially. In 1990, Robin Holiday updated this definition. And he took into account what we started to know in basically 50 years of science, and said that as epigenetics is really the temporal and spacial control of gene activity during the development of an organism. The definition that we will use for this course, and it's commonly used in the epigenetics field has a little bit more molecular detail to it. And so our current definition is really based on that of Art Riggs. And it said that epigenetics is the study of mitotically heritable, and this is important, mitotically heritable changes in gene expression that occur without changes in DNA sequence, and this is also very important. So we're not talking about changes in single nuclear type polymorphisms, for example, that exist between people. But rather we're talking about changes that don't require those genetic changes. They occur without genetic changes, with no change in the DNA sequence. The mitotic heritability is important, and we're going to deal with this in the coming slides. but this is something that's quite controversial in the field of epigenetics. There are those that say that this is not actually required for an epigenetic mark, although I think the majority of the field would say that it is. So, we'll stick with the definition in this course that it's in general required for mitotic heritability. But I will introduce a couple of examples, and explain about those that aren't necessarily mitotically heritable. So lets think about this mitotic heritability and what it really means. Well if you take the single cell here and when it divides if it copies over all of the epigenetic marks that it has to its two daughter cells then those epigenetic marks will bring about the same changes in gene expression or the same gene expression profiles and so the two daughter cells will have the same phenotype, the same function as the parent cell, and so on for the next generation. So, this epigenetic heritability, the mitotic heritability means that the same sets of genes will be expressed in the daughter cells, as I just said, but also ensures tissue homogeneity. So if you think of a liver cell, when it devides, it should produce more liver cells so that we have a liver that is homogenous and is always made up of liver cells and nothing else. If you take away the mitotic heritability, this aspect of epigenetic control, then when we have this same liver cell what happens now is that the resulting progeny cells will have a different set of epigenetic marks, and therefore, a different phenotypic outcome, a different function and this will result in different cell types. So here, you know, this green cell and the purple cell, and the result of them could result in, again, a wide variety of phenotypes, in the particular cell and therefore functions. So, this would mean that you would have tissue heterogeneity, a wide variety of different cell types all found in the one location. And we know that this isn't usually the case. So it's mitotic heritability that will allow cellular identity to be to be maintained. So as I mentioned earlier, this heritability and this mitotic heritability throughout development is also counted by particular periods when epigenetic marks are removed. So, I mentioned earlier that this happens and this is shown here by this break in the slide, that it happens in the germ cells and also it happens for a second time in early development. If you think about why this might need to happen I think it makes quite good sense. The somatic cells from which an egg or a sperm are derived are really nothing like an egg or a sperm. And so we need to remove the epigenetic marks that are found in each of those cases and lay down a fresh set of marks, that are unique to the egg or the sperm to allow the expression of the genes required for each of these cell types. Similarly, once this egg and sperm have gone on to form the zygote, then we need to remove the epigenetic marks that were found in the egg and the sperm that were specific to those particular features. And now lay down those that are required to make a totipotent cell mass that can perform all of the cells or all of the different types of tissues in the adult organism. So, these are the two, what’s generally considered as epigenetic reprogramming, which we'll go into more detail in the later slides, but epigenetic reprogramming or remodelling and removal of epigenetic marks also happens at particular other time points within differentiation. And these ones are perhaps less well understood or studied at the moment but we certainly know still occur.
