So welcome to the course on epigenetic control of gene expression. My name is Marnie Blewitt and I work on exactly this topic here in Melbourne in Australia. So in general what we're going to do is go through and explain some of the details about epigenetic control and use this to explain some epigenetic phenomena that occur in mammals with also some highlights of what occurs on lower organisms. One of the examples we're going to talk about is X chromosome inactivation, and this is really a fascinating process by which a whole chromosome in a female mammal is densely packaged down and gets set outside of the nucleus unused. It occurs so that you can have dosage compensation between females that have two X chromosomes and males that have one. We're also going to think about how aberrant epigenetic control can contribute to disease. For example, cancer. And in later lectures, we'll think about how epigenetic information, so information in addition to the genetic information might be passed between the generations. So, can you really inherit something from your parents that's more than just the DNA? We'll also think about how the environment, and particularly the diet might alter this. So, throughout these lectures you might find that you feel you need a little bit of additional background information. There are links on our course site to additional background reading and this could be used to catch you up a little bit, or to further broaden your understanding of what we cover in the lectures themselves. You'll also find in these same locations will find your homework assignments that will occur on a weekly basis. Plus in most if not all of these mini-lectures, you'll find in-video quizzes to keep you up to date and to make sure that you're understanding as you go through your course. So let's start with the general introduction, and to generally think about what we're talking about when we say epigenetic control. So for decades it's really puzzled biologists as to how it is that you can have the single genome which is contained in the single cell fertilised egg give rise to the hundreds of different cell types that are found in embryo or even an adult. So you have the same book of instructions, the same genetic code, and yet so many functional outcomes, or so many phenotypes for the cells. Back in the Medieval times, they actually thought within the head of the sperm, was a tiny, fully formed human, called a Homunculus. And that the egg really, and the mother really just grew this tiny human. But of course we now understand this is not the case at all. And rather, what happens is that there's additional information on top of that genetic information which really allows the formation of each individual cell type, despite the same book of instructions that occurs, that exists within each of these cell types. So, scientists have used this term, epigenetics, with the prefix epi, just meaning a layer of information on top of the genetic information, just like our epidermis is the outer layer of our skin. So, it's this epigenetic information, this additional information, which allows the development and differentiation of the hundreds of different cell types, all from the same set of instructions. What we now understand is that each of these cell types is defined by the genes that are expressed within each cell. So gene expression, that I'll use this term many times throughout these six weeks of lectures, really refers to the transcription of the DNA into the RNA. And then from the RNA translated into the protein. And this is what we really are talking about with gene expression. So each cell type can actually express a restricted subset of genes. So while the mammalian genome has around 25,000 genes not anywhere near 25,000 are used in an each cell type, at each time. There's a huge number of combinations that you can pull out of say, a few thousand genes, that are expressed in each cell type. Many different versions of that, when you have 25,000 genes to choose from. And it's this particular set of genes that are chosen to be expressed within each cell type that really define their function. So if we think about that with just three cell types in mind, we can think in a neuron we know they make dopamine, this signalling molecule, but they don't make haemoglobin or myoglobin. Haemoglobin, on the other hand, is made in red blood cells and this is the protein of course thats required to traffic oxygen around in the body. But, red blood cells don't make dopamine or myoglobin, and finally in muscle cells they do make myoglobin but not hemoglobin or dopamine. So while here were just thinking about three genes. This happens on a genome-wide context for all 25,000 genes, and you have the expression of these restricted subsets of genes which enables the phenotype and the function of each cell. So then the question becomes, well, if each cell type is defined by the genes that are expressed, how can a different set of genes be expressed within each cell? How does the cell know which one to make, which genes to express? And this is by a combination of two things. It's the activity of transcription factors that are specific for each cell lineage. So, by that I mean these proteins that have sequence specificity in their binding. And, they bind to their promoters of genes to allow and activate or repress the expression of particular genes. So, there will be transcription factors which are specific for red blood cells and they will help to drive the expression of the haemoglobin gene. But it's not only these lineage specific transcription factors. They need to work within the context of broader information and this broader information comes in the form of epigenetic marks within the genome. And it's these epigenetic marks that we are going to concentrate on in this course. So, what is an epigenetic mark? What do we really mean by epigenetic marks? Well these epigenetic marks, or epigenetic modifications, can really be considered to be very similar to punctuation marks in language. So we know the English language is a string of 26 letters. But when you think about the genome sequence, the genome's language has only four letters, A, C, G and T. The four bases. The reason that we can see within English what we're writing, is because of formatting. So we see within these letters that are at the top here and made into a sentence, we see that we can see each individual word because of spaces between words, we can see the beginning of the sentence with a capital letter, and the end of a sentence with the punctuation that's at the end, the full stop in this case. If we remove that punctuation mark and the formatting it's then much more difficult to see what's being said. We know what's being said, probably because we just read the sentence. But if you now put up a new sentence without any punctuation, then it's much more difficult to interpret what's said there. And this is in a case where we have 26 letters, so we have more variety. But in the genome we have just four, and we have much longer strings, we have billions of base pairs, so billions of bases rather than you know tens of letters that are showing here. This sentence just says a lack of prior knowledge makes the challenge greater. So it's this formatting and spacing and the punctuation that really allows us to see each individual word that makes up a sentence. And interpret the information that's there. So, epigenetic marks or epigenetic modifications perform a similar role in the genome. They allow us to interpret the information that's there in those 4 bases in the billions of letters that are around. So there’s several things that the epigenetic marks do. First of all they mark the beginnings and the ends of the genes, the start and end of the gene, just like the beginning and the end of a sentence. They also allow you to see the pieces of information that are within the gene. So just similar to how you can see words within a sentence. They also provide structure to the chromosome, that's a little bit like paragraph marks or like chapter breaks. So they help to show the beginning and the end of the whole chromosome and also the centre. And this provides great structure for the chromosome and means that the chromosome will be folded up correctly. And finally, and this is what we'll tend to be focusing on for this course, they actually alter how we read each gene. Just like the punctuation marks do at the end of each sentence. We know that there are punctuation marks or epigenetic marks that are associated with a gene that's silent or inactive. For example, like the full stop at the sentence that's straight on this page. But we also know that there are epigenetic marks, punctuation marks that are associated with active genes like exclamation marks, which say: Read me now, use me now. And that means the gene is being expressed. But there can also be more subtle nuances, more subtle changes. For example, like a question mark in English, this will change the intonation that you use when you read the sentence, and it will also change the meaning. Or an ellipses in a similar way. So in summary then we know that these 3 different cell types which are currently
considering have different sets of genes being expressed. And these different sets of genes really define the cell that's made. The reason that different sets are to be expressed is partly because of the epigenetic marks that are found on the genes that are expressed, or not being expressed. So for example, the haemoglobin gene in red blood cells is epigenetically active. It has exclamation marks covering the promotor of this gene. But dopamine and myoglobin are epigenetically inactive, so these these genes have full stops covering the genes. By contrast then, a muscle cell will have myoglobin being epigenetically active with the exclamation marks, but now those full stops will be placed over haemoglobin and dopamine. So, epigenetic control allows or permits these differential expressions of genes within each cellular lineage, and therefore permits the development and differentiation of hundreds of cell types from the single genome.
