Introducing epigenetics

[Music] my name is Gemma um I work up at ECU educating um uh first and second used units in a variety of different genetics units um and one of the most complex topics we come across when we do genetic studies is epigenetics so hopefully today I'll be able to maybe Focus the attention on what's really important in epigenetics and what we really do understand at this minute and show you how uh useful epigenetics will be uh in the future um so epigenetics is a layer of control we have um on top of the genes so we've got our DNA sequence and epigenetics forms a layer of control which determines which genes are turned off and which genes are turned on in particular cells in the body um we do this they do this by making chemical modifications to either the DNA itself or to the proteins that the DNA interact with um and making the DNA either accessible or invisible to the uh transcription Machinery um so it's just like sticking a chemical on or off switch on the DNA saying you're going to be turned on you're going to be turned off we don't need you um the reason this is important is because every single cell in our body apart from red blood cells has exactly the same DNA sequence so cells in my eye cells in my skin cells in my liver cells in my heart all contain identical DNA but obviously the functions of all these cells are different um and epigenetics is the first layer of control which says to perhaps a brain cell or you can shut off all the functions that make insulin you don't need those um so it helps us develop um as a human into a large multicellular organism with lots of different cells having particular specificities and particular roles in the body if we didn't have that epigenetic system turning stuff on and turning stuff off all the cells in the body might be expressing all the things all the time and it would be absolutely chaos um so we need that layer of control to say right you're going to be a brain cell you're going to be a kidney cell you're going to be a liver cell switch off everything you don't need and help to develop that function um so in every single cell in our body we've got 2 meters of DNA approximately so taller than me an extreme amount skinnier than I am um all compacted into the nucleus of every single cell um to help in that compaction the first thing that we do with DNA is we break them down into chromosomes so humans have got 46 chromosomes 23 you inherit from Mom and 23 you inherit from Dad and that helps convert that long 2 m piece into 46 little shorter pieces um and that's the first level of compaction to try to get the DNA into the cells um so like I said before uh every single cell has the same DNA but every single cell has a completely different function um and the expression patterns of the different genes are different in each particular cell type so you're going to get um enzyme secreting cells in your intestinal epithelia to help you break down the food you're certainly not going to get uh food breaking down enzymes being released in your smooth muscle cells it's just not how everything works every cell has its own specified function and that specified function is determined by which genes are on and which genes are [Music] off um the good thing about the epigenome is that it is changeable so when things happen and you need to turn on expression of genes which you currently have turned off in cells you can actually alter that and modify things um this is particularly important during development so say when the sperm and the Egg very very first get together you need a lot of stuff expressed at those very early stages of development that you don't need again once you're past say three months of gestation so the fact that we can turn things on and turn things off is really really important um and is why the change abil uh the flexibility of the epigenome is really important um so the cells are constantly listening for signals to change what they're doing so one um all the sort of signals we can get are from inside the cell from neighboring cells or from the environment and depending on your stage in development will depend which signals are more important um so when the sperm and the Egg first get together and the cells start to divide then the signals from the neighboring cells provide the information to say right I'm going to be external layers I'm going to be internal layers and those internal signals are the ones which start the development but as you grow older things in your environment play much more of an influence on your epigenome so things as uh like your diet uh even the season what diseases you've been exposed to whether or not you use drugs whether or not your exercise all of those things will influence your epigenome and can change the patterns of uh controls that you have laid down on your genes so it is changeable it's influenced by a lot of things um and as you get older the environment is probably the most significant influence on your epig genome um the other important thing about epigenetic signals is that they get um erased when the sperm and the Egg get together um when the sperm and the Egg get together both of them contain the epigenetic signals from their parents so the egg contains mother epigenetic signals the sperm contains the father's epigenetic signals and when they come together uh you need to erase all those signals so that all of the cells that form that new embryo have the possibility to become anything if they have if they remain with their um egg and sperm tags first of all you'll get conflicting tags between moms and Dad's um chromosomes but also they've already sort of down a path of development and you wouldn't be able to go back and create all the tissues and organs that you need to in the developing embryo um so when they first get together the um methylation or DNA methylation happens really really rapidly off the sperm DNA um and it goes a little bit more slowly off the egg DNA but that's purely because you need a couple of those methylation tags to get that cells to to do those first couple of stages of cell division um but by the time we get to the blast assist stage where that um fertilized egg is ready for implantation all the DNA methylation signals have been wiped and all of the cells in that little blasy can become anything whatsoever so when we're talking scientific research about embryonic stem cells these are the ones we look at and these are the ones researchers try to figure out what Drive cells down particular Pathways so that if you took some of these embryonic stem cells you could make them into a liver or you could make them into a neuron or you could make them into an eye cell um it's these embryonic stem cells which have the ability to become anything which are so promising in medical research um once the embryo gets to um recognizable baby shape uh all of those DNA methylation tags for tissue specificity are all laid down so all of the cells in the liver have liver tags all of the cells in the heart have heart tags all of the cells in the brain have brain tags so all of those ones that Define tissue specificity and what those tissues are going to um M be maintained and develop into have all been laid down by the time the embryo is recognizably baby-shaped um another thing that's really important with the epigenome is that it remembers um you need to uh make sure that cells that have started down One path of development don't go backwards so if your cells got some signaling from neighboring cells saying I'm going to become part of the nervous system when that cell then divides and creates two new daughter cells you don't want those daughter cells one to go hey actually I'm going to be a lung cell or no I think I might be a muscle cell so when the cells go through division those methylation patterns those epigenetic changes are maintained from generation to generation and then the environmental exposures or the signals they're getting build upon those previous um exposures so what we've got here is a stem cell in the embryo it first gets a signal from its neighbors to say okay I've got a couple of cell neighbors around me I'm going to have to be inside I'm going to be have to be an internal cell um get some signals saying become nervous system so when that cell divides it then passes those signals onto the next cell and that can build upon that and that cell might get signal saying become spinal cord and then it might get signal saying don't become a gal cell send out axons and then in the end it'll get signals saying become a motor neurone and that's how it builds upon those epigenetic tags from previous cell Generations um so epigenetics prevents the cells from going backwards if we didn't have these epigenetic tags it would be just like cells expressing things all the time everything would be utter chaos and we wouldn't be able to develop this really complex interacting system of tissues and organs that all function together to make us people um so I mentioned before the epigenome is changeable and one of the biggest influences on your epigenome as you get older is your environment so direct influences such as your diet can affect your epigenome um if you have a healthy diet you will have different epigenetic pattern than somebody who has an unhealthy diet you'll have different genes which are switched on and different genes which are Switched Off um but your um epigenome can also be influenced by indirect environmental changes so things such as the amount of stress in your life um when you were growing up whether or not your parents fought a lot all of those sorts of things can have an influence on your epigenome um one particularly good example about how nutrition influences the epigenome um is found in bees uh queen bees and worker bees are genetically identical they have exactly the same DNA the only difference is that queen bees are force-fed royal jelly from the minute they're at the lavel stage and the worker bees are fed on nectar and pollen and water um the fact that the queen bees are fed on Royal jelly switches on jees in her that helps her to to develop ovaries and a really really large abdomen F laying eggs and gives her a really queenly attitude which sort of get makes the other worker bees do what do what she wants basically and the only difference between these two types of bees the DNA is identical to only difference is the queen bee gets fed royal jelly so her diet is switching on particular genes to develop her ovaries and her abdomen and they the um worker bees remain sterile so it's that's all completely epigenetic changes related to [Music] diet um so let's go back to how all this works um the way it works starts largely with uh the DNA winding and the proteins that we use to do that that and compact the DNA into the cells um the first level of DNA winding is obviously the helical shape of the DNA that starts to compacted a bit um but in order to get it right inside the nucleus uh we wind the DNA around proteins called histones um now we get eight of these little histone proteins together to form a little ball we'll call it um and the DNA winds itself just over one and a half times around each ball uh to form what's called a nucleosome and then the nucleosomes W around one another and they wind around one another and they wind around one another and they Compact and Compact and compact until they form uh the condensed or semic condensed form of Chromatin which you see in normal uh resting cells and then when the cells go into cell division and the DNA compacts even further to form those classical chromosome shaped structures that we all recognize um so this is all based on DNA winding around histones and histones winding around one another um so the first type of modification we have are called histone modifications and those take place on the taals of these little histone proteins that form that nucleosome help form that nucleosome so each of these histone proteins has a tail that sticks out the side and each of these Tails has various points at which you can add different chemical signals this is where epigenetics gets complex um there are a number of different chemicals you can add to the tails you can have uh acetol groups you can have phosphate groups you can have methyl groups and you can have ubiquinone groups the position of each of these tags and uh the position on the tail and whatever is lying next to it greatly influences what these particular chemical tags do um so when we talk about DNA methylation later um DNA mation always turns off DNA expression gene expression but when it comes to histones it's not that clear you can have uh methyl groups on particular positions in this arm and this arm which will actually unwind the DNA and help gene expression or if you put them on this arm and that arm over there it will wind up the DNA and turn off gene expression so the only really sort of solid thing that we can say is that if histone tails are acetylated DNA is Unwound exposes the genes uh to the transcription machinery and increases expression it gets much more complicated when we're talking about the methyl groups the ubiquinone groups um and the phosphate groups the the positions of those particular groups and where they are and how they interact with one another can either open or close um the DNA and that is a really really emerging field of epigenetic research trying to find which combinations will open and which combinations will close um but as a overarching statement we can say acetalation opens the DNA so it basically changes es the charge um on the nucleosomes and forces them apart from one another unwinds the DNA makes it looser and allows access to the genes for the transcription Machinery in the cell um so it either exposes or hides the genes from the cell so a cellation opens some of the other modifications will close um and then you have access to the genes or no access to the genes um when the DNA is open also the nucleosomes can move along the genes or along the DNA stretch so they don't have to stay exactly where they are they'll open up and then they'll go actually the Gen I want still wound around here or just Shuffle down a bit like that so the hisone modifications are ridiculously complex but if we make the overall statement that acetylation opens the DNA allows for expression um the second type of modification happens to the genes themselves um and when we talk about genes these are small sections of the DNA which provide instructions for creating a protein the protein then goes and does its job either in the cell out of the cell in another organ wherever it's sent to go um and the gene itself is made up of three different bits we've got our RNA coding sequence in the middle here that's the information that codes for the protein um and at either end we've got a promoter and a Terminator basically as the colors suggest promoter says this is the start go from here the Terminator says this is the end stop here um in addition promoters have a couple of sequence in them which help to regulate the activation or suppression of genes um there's a number of different sequences where other proteins will bind and either really amp up the expression of the gene or really slow down the expression of the gene um and one particular area of the promoter um there is a high number of G and C bases so it's called a cpg island where there's lots of C's and lots of G's um and in this particular area uh methyl groups are able to bind to the cyto residues when they bind to the cytosine residues they basically block transcription so um it's like putting a methyl group on the top here the transcription Machinery can now no longer see the Gene and no expression happens so DNA methylation is a lot easier DNA methylation turns off genes easy as um so what we have here is like a little example we've got C cine cytosine residues um in front of the promoter here when they're empty they don't have anything attached to them we get marvelous gene expression when they're methylated the transcription Machinery can't actually see that promoter can't determine the start of the Gene and the gene doesn't get expressed so uh genes are Switched Off when the the promoters are [Music] methylated um so Research into epigenetics is quite difficult because of all the influence of the environment it's really really hard to say what's influenced one person and what hasn't influenced another person um but a perfectly good uh study is to look at identical twins so identical twins are formed when the sperm and the E get together they create one embryo and then the embryo splits creating two genetically identical individuals so their DNA is all accounted for is identical between one twin and the other twin the only difference that we see then is in the EP epigenome and theep genetic patterns that they carry and these can vary enormous enormously even between identical twins um so what we've got here is some chromosome pictures of uh a particular pair of chromosomes from a set of identical twins one twin has had their DNA methylation pattern colored in red one twin has had their DNA methylation pattern colored in green and then the two images have been overlaid wherever there's yellow identical methylation so at age three the two identical twins have almost 100% identical epig genome or DNA methylation there's a couple of areas you see a little bit of red poking through here a little bit of green poking through here that might be from something as simple as uh one baby learning to roll over first having a different environmental experience like that one baby perhaps getting a few more nutrients through the placenta small little changes like that but at age three pretty much identical epigenomes 4 7 years later and the pattern changes remarkably so again we've got a pair of 50-year-old identical twins uh we've taken one pair of their chromosomes colored one red colored one green overlaid them and everywhere there's yellow identical methylation and here you can see lots more green and lots more red poking through in that overlay and this is because even though twins are identical they don't share 100% of their environmental influences you might have one twin that likes to play soccer and one twin that likes to play net ball and something as little as that can be enough to change the EP genome different friendship groups one twin smokes one twin prefers to read rather than watch Telly every single thing that they're exposed to can alter their epig genome and what genes are turned on and what genes are turned off um so identical twins are a fantastic way to determine whether or not there is an environmental um element to any particular characteristics um and one characteristic we look at here is IQ so we've got identical twins reared together so growing up in the same household um have an 85% correlation of their IQ if IQ was purely a genetic determined by genes it would be a 100% correlation so the fact that they're not 100% correlated means there's something in the environment that is influencing the IQ of these kids and we can see if we go down further um we've got identical twins reared apart so in different households now have have just over 70% correlation in the IQ so there's definitely something happening in the environment which influences the IQ of these kids um and identical twins are fantastic to figuring out all these environmental influences and whether or not environment plays a role in any particular characteristic um so for identical twins diseases are not always the same between identical twins you might hear the um phrases concordant and discordant so concordant means if one twin has a disease the other twin also has it discordant one twin has the the disease and the other twin doesn't have the disease and discordant twins are fantastic for studying in research because you try to figure out what's different between the Twins why is this one have the disease and why doesn't that one have the disease um so it can be simple things like before one kid plays sport the other kid doesn't one kid might have gone to China and been exposed to high pollution levels their epigenomes changed and now they have uh a more uh they have an asmatic type phenotype whereas the other kid didn't go to China and they're fine um so looking at the difference in the methylation DNA methylation pattern and the other the histone uh modifications is a very very emerging field of epigenetic research um and twins are a fantastic resource if we can use [Music] them um and the last thing I want to talk about is the um the forward prospects for things such as epigenetic research um epigenetic therapy is one of the um promising targets of the future because it seems a lot easier to turn genes on and off than it does to change DNA sequence um and there are actually quite a few drugs that have been approved for human use and or underdevelopment altering the methylation patterns of the DNA or trying to adjust um histone modifications um the only thing that we need to be aware of is that treatment needs to be selective so you have to Target the exact cells that you're looking for um otherwise if you turn off a gene in all the cells in the body well turning it off in the cells in the lung might be fantastic but turning it off in the kidney or the liver might actually create cancer so you've got to be really really selective with the targets and what they're actually aiming for um but epigenetics is a really really promising and emerging field of medical research and trying to influence the way people develop disease and manage disease so that's it for my talk but I didn't forget this week here's my analogy we have two cells in the human body this is the mom's coming over for dinner cell and this is the I'm having a bunch of friends over for Christmas dinner cell both of them have identical recipes or identical DNA the individual recipes are the genes and we've got lots of different um epigenetic modifications which determine which genes are going to be on and which genes are going to be off so in the mom's coming for dinner cell I have histone modifications here that are cramping up that those lots of DNA so I can't read them and Mom's going to be getting the chili salt and pepper Seafood Jee expressed for her meal histone modifications compacting all that DNA she's also going to get herb chummed lamb racks for her meal but she's not going to get whatever this is because this has been DNA methylated and I can't see what it is so histone modifications here compacting all the DNA together and she's going to get a walnut and ricotta stuffed figs for her dessert that's our mom's coming for dinner cell I'm having a bunch of friends over for Christmas cell has DNA compacted at the start they're getting pork fillet and Panetta kebabs but not what this is cuz that DNA methylation is over that recipe I can't read it more hisone meth modifications chicken and tomato feta patties with spinach salad but not whatever that is DNA methylation won't let me see it they're getting lime and chili roasted snapper they're getting tomato mustard and beef with baby fennel they're getting a BLT salad and they're getting a hazelnut tiramisu but not whatever that is cuz that's methylated or not whatever that is cuz that's methylated and they're getting peirs with chop mint sauce so even though the hisone modifications might allow the DNA to be open and accessible um DNA methylation can actually turn off genes in those strips as well so you might have a stretch of DNA that's Unwound then might be 10 genes in there but you don't need all 10 of them you might only need six so DNA methylation will methylate those four that you don't need and you only get the use of six of them any [Music] questions

Channel: spiceuwa

Views: 45,049

Keywords: epigenetics, twins, DNA, epigenome, methylation, histone

Id: 3Mg70zOd8yA

Length: 24min 53sec (1493 seconds)

Published: Mon Mar 14 2016