So what we've thought about this week is that epigenetic reprogramming occurs between generations. And so while the hallmark of epigenetic marks is that they are mytotically heritable this mytotic heritability is countered by periods when these epigenetic marks are actively or passively removed. So this predominantly occurs, this, this epigenetic reprogramming predominantly occurs in germ cells and again in early development. However, these aren't strictly the only periods when epigenetic reprogramming occurs and epigenetic marks are removed, because we also know at particular time periods during development, for example, during differentiation from particular stem cells, or for particular cell types, for example from the blood stem cell, making different type of T-cells, for example. We know there's active remodelling of epigenetic marks during these processes, but what we've concentrated on is these these two waves of epigenetic reprogramming that occur in the germ cells in early development. So let's just again, go through what happens during these periods. We know that the first wave occurs in germ cell development. So that's when these primordial germ cells, which are first formed in about the mid-gestation embryo, it's when these develop and go through their appropriate maturation so they've gone from being a diploid cell into a haploid cell and in the end form the final functional sperm and oocyte. So it makes sense that the genome is reprogrammed at this time, because you want to go from a somatic cell, with its own particular epigenetic marks, to a germ cell, these very specialised cells with their very specialised functions. So the paternal and the maternal genomes in general are cleared and reset at this time. But apart from this really generalised clearing, we also know the repeats and in particular in mouse, the IAPs is what's been most predominantly studied. These don't tend to be cleared. We need to keep these repeats silent in general so that they don't jump around the genome and cause destruction. In this way all the data aren't expressed and causing transcriptional interference with the surrounding genes. What we spent a lot of time in this last week thinking about is what happens to the imprinted genes. So we know that the imprinted genes during this primordial germ cell development are cleared and reset. So the maternal and the paternal imprints are removed but then the resetting occurs differently depending on whether you're developing sperm or developing eggs. So if you're developing eggs then both of the alleles, when the cell is still diploid, or the single allele, which is found in the haploid egg will end up having maternal marks. All of those paternal marks have been cleared, and now the resetting happens just to leave maternal imprints. The reciprocal happens in the sperm. So now in the sperm you have solely paternal marks. This then means that when you come to fertilisation and the sperm and the egg come together to form the zygote, this then ensures that you have one copy of the allele that has the paternal marks, and one copy of the allele that has the maternal marks, and this is what's essential for normal development at these imprinted genes. We then move on to think about what happens in preimplantation development. Again, the sperm and egg are very specialised structures, so we need to remove the epigenetic marks associated with these germ cells, and lay down appropriate epigenetic marks for embryonic development. And so what we see is that the paternal and the maternal genomes are cleared and reset. But what we went through is that this clearing and resetting has different dynamics depending on the genome. So, the paternal genome, the one that's come from the sperm, is cleared very rapidly and actively involving tet proteins. Whereas the maternal genome is cleared more passively over time and this happens basically because you have DNMT1 excluded from the nucleus, so you're not maintaining methylation. The IAPs, the repeats are still not cleared, for safety reasons, if you like. But now the imprinted genes, instead of being cleared like the rest of the genome, they're left untouched. So it's at this time that they maintain their parent of origin-specific marks, and this is really essential for normal development. They need to keep that mark, which marks them as coming from the paternal germ line, or the maternal germ line, and if they were to remove the epigenetic marks that they received when they were developing sperm or developing eggs, then the two parental genomes would no longer be distinguishable from one another. So the imprinted genes are only cleared once during germ-cell development. We know that this can go wrong. So if in some way you, you disrupt the effect of the imprinted gene so that you don't have the one allele being expressed and the other silenced, then you end up with an imprinting disorder. And the disorder that results really depends on which gene is affected, and whether or not you've have now biallelic expression or biallelic silencing and these can have different results. But how those imprinting disorders come about can be many different ways. So it could be through a genetic mutation meaning the imprints aren't established correctly in the first place, or it could be through genome duplication and deletions. So you end up with what's known as uniparental disomy. So for example, it will look like you have two paternal alleles and no maternal alleles, would be uniparental disomy where it's the paternal chromosome that's being duplicated. And finally in the most, in the rarest of circumstances, imprinting disorders can happen because you've had a fairly over-appropriate epigenetic reprogramming so it can have a true underlying epigenetic basis rather than a genetic basis for these imprinting disorders. So next week what we're going to start to think about is how epigenetic reprogramming can go wrong, and the consequences that this has on development. We're going to consider this in the broader context of how the environment influences epigenetic control.
