DNA is a curious thing. It might make sense for you to think about the DNA in your brain in terms of “brain DNA” and DNA in your blood in terms of “blood DNA”, but you’d be wrong. Strangely, the DNA in your skin cells sloughing off to make up a considerable proportion of common household dust is the exact same DNA found in the rest of the cells making up your body and bodily organs like your brain, heart, liver and muscles. So how does DNA know to make neurons or finger nails? How does it know what to do and where to do it? The answer has something to do with a field of study called epigenomics (1, 2). Epigenetics is what allows identical genomes (genome = your set of DNA) to display very different phenotypes (observable characteristics) (3, 4). Epigenetics allows us to make different cell types out of the same DNA, makes identical twins different and explains how the calico cat got its spots.
First; DNA. In case you were wanting to nerd out, DNA stands for deoxyribonucleic acid. Generally, you probably try not to think about DNA too much, and just kinda hope it does whatever it is it’s supposed to do without turning into cancer. If you’ve ever wondered what DNA actually is though, it’s just four different (yet very similar) chemicals called nucleotides, distinguished by one of four chemical modifications called nitrogenous bases. Their names are Adenine, Thymine, Cytosine and Guanine, but you can just call them A, T, C and G. And they pair off bound together in the following way; A’s with T’s and C’s with G’s to make DNA a double stranded molecule over 3 billion base pairs (2 meters!) long. That’s 3 billion base pairs per cell, and you’re made up of trillions of cells. Every time a cell divides, these 3 billion base pairs are replicated.
If grade 12 biology was a long time ago and the word “replication” makes you feel ill here’s a helpful synopsis; DNA is transcribed into (makes) mRNA and mRNA is translated into (makes) proteins. Another way of talking about DNA being transcribed into mRNA is to say that the DNA is being expressed (turned ‘on’). Conversely, when DNA is not being expressed or transcribed into RNA, we could say that it’s transcriptionally silent (or ‘off’). So every time your cells divide, they generally duplicate the 3 billion base pair sequence making up your genome with each round of division. Chunks of these nucleotide sequences make up genes, of which you have about 25 000, averaging in the range of thousands of base pairs in size. DNA lives in a sectioned off little bit of cellular real estate called the nucleus, and it’s distributed into little manageable packets called chromosomes of which you have 46. You have 22 different chromosomes, numbered 1 through 22 from biggest to smallest (chromosome 1 being the biggest). 22 come from your mom and 22 from your dad. You also have 2 sex chromosomes, one from each parent. If you’re a girl you have two X’s and if you’re a boy you have one X and one Y. You get your X chromosome from your mom, and either an X or a Y from your dad depending on whether you’re a boy or a girl (22+22+ an X + (a Y or an X) = 46).
If you’re stuck on the idea that 25 000 genes doesn’t sound like enough to make something as complex and wonderful as yourself, you’re onto something. Your genes actually only account for about 3% of your entire genome- so why spend all of that energy replicating 97% of 3 billion every single time your cells divide when we’re not even using it?! Well, without that stuff our genome would be pretty dense, with all of the important bits all squished together. But with all that extra DNA, our genome can be organized and neatly packed (all 2 meters) nice and tight into our cells, and still be accessible to the proteins whose job it is to transcribe our genes. Also, since random DNA mutations can and will happen, it’s a better strategy to have a whole bunch of cushion- you’re less likely to be hit by a bullet in a huge crowd of people than if it’s just you and the bullet in a very small space.
Epigenetics can roughly be translated to mean “occurring on top of DNA”. It has to do with a level of regulating DNA expression via regulating the availability of DNA to the proteins (transcription factors) that turns genes on. Your DNA is packaged in your cells unlike anything imaginable, and the organization and accessibility of this DNA is at the crux of epigenetics. Just by changing the way DNA is folded and coiled up, allows our cells to express very different phenotypes without altering the DNA sequence itself. Imagine you were given 25 meters of thread and asked to fit it into a golf ball, yet in a way that allowed you to unfold and refold certain parts of the thread at a moment’s notice. You would probably want some kind of device, like a spool and lots of them, to help you keep track of what’s what and where and to allow you to unroll particular bits of thread without unrolling the whole thing. You can see how this would be extremely difficult (I can’t even fold a map back properly without totally spazzing). Yet our cells do this all the time. They have special kinds of spools made of proteins called histones. These spools are super high tech, and their movements are controlled in part by a special code called “the histone code”. Our DNA is threaded around these spools into highly compact packages called chromatin. In this way, the spools control the accessibility of our DNA to proteins (transcription factors for example) that want to land on the DNA and start working (transcribing). For example, if two histones roll away from each other, this “opens up” the DNA between the two histones. We would call this formation an “open chromatin configuration” otherwise known as euchromatin. Euchromatin is a way of talking about DNA that is wrapped around histones, but otherwise accessible to the proteins whose job it may be to turn these genes on. Conversely, if the spools are so close that they’re touching, the DNA wrapped around them doesn’t have a very good chance of being turned on because it’s inaccessible to transcription factors. Chromatin that is in this configuration is called heterochromatin, and we would say that the DNA located in heterochromatin is effectively “silenced”; epigenetically silenced.
If you were wondering about the special code, “the histone code”, controlling the formation of euchromatin or heterochromatin, it’s located on the tails of the histone proteins. Technically, one “spool” is made up of four different kinds of histone proteins x 2 (for a total of 8 histone proteins). Their names are H2A, H2B, H3 and H4. Each one of these proteins has a “tail” (a string of amino acids hanging off the end of that protein). This is where the code is programmed. The code consists of the addition or removal of particular chemical modifications to those amino acids including; acetylation, phosphorylation, ubiquitination or methylation (1). It doesn’t really matter if you don’t know what these are (methylation is just one carbon group with 3 hydrogens attached to it for example), what matters is that the open or closed formations of chromatin are regulated by what modifications occur on what amino acid in the tail. For example, if you have an acetylation on the ninth amino acid (a lysine for example) on H3, then the chromatin formation will likely be ‘open’ and the DNA located there will be open for business (1). A certain class of protein catalyzes the formation of these modifications.
Remember when I said that we only really use 3% of our genome? That’s 3% of 3 billion base pairs. If you were wondering what all that extra stuff is and want to know how it got there, you may find the answer a little unsettling. Most of it (~ 50%) is a bunch of weird viral DNA and huge expanses of repetitive DNA that mostly doesn’t code for anything, and it’s been accumulating in our genomes for billions of years (1). Yeah that’s right, viruses. But don’t worry, we’re epigenetically silencing them! Many of these sequences are wrapped up, nice and tight, safely tucked away inside piles of heterochromatin, but that’s not all. Another way our cells epigenetically silence certain parts of DNA is by chemically modifying it.
I know I said earlier that epigenetic regulation does not involve altering the DNA sequence itself- and it still doesn’t! Not technically anyway. What we’re doing here is just adding a methyl group (1 carbon and 3 hydrogen’s worth) to the cytosine nucleotide (the C) (5). This may not seem like a biggie to you, but to the proteins that land on the DNA it’s a big deal. Much of the function of a protein is based on its shape, and some of the nooks and crannies in a protein are absolutely crucial for its ability to function. A transcription factor is a protein that has a nook (or cranny) that only has eyes for a very particular sequence of DNA. Sequences of DNA located at the beginning of a gene (the promoter region) are what the transcription factors are looking to land on. It’s like that sweet spot on the sofa your butt has impressed upon it over the years- your butt knows it. Okay, so your butt’s the transcription factor and that sweet indentation in the sofa cushion is the promoter sequence of the gene. Like the specificity of a transcription factor to a particular gene’s promoter sequence, your butt only has eyes (eye?) for that spot on your sofa. For the transcription factor, methylation to a C located in that promoter sequence is like you sitting on the remote control or a fork or something when you plop yourself down on that spot. You’re going to get up, fast. And that’s just what the transcription factor does- it doesn’t even sit down, it doesn’t recognize that sequence anymore because it feels awkward, even though that C is still a C and the rest of the A,T,C and G’s in that sequence are fine. So just by adding a methyl group to the C, we’ve effectively silenced that gene too, because we made it so the transcription factor won’t sit down. So even though that gene may appear open for business, it’s been epigenetically silenced by methylation. There are enzymes that catalyze the addition of methyl groups to C’s, called DNA methyltransferases.
So not only is all of that weird DNA (that we don’t really want or need and are afraid of) in our genomes epigenetically silenced by heterochromatin formation and methylation, some of our friendly neighbourhood genes are silenced too. This is in part how you get different cell types from the same DNA. You epigenetically silence some of your liver specific genes in your skin cells, your muscle specific genes in your neurons, and your fingernail genes in your eye etc. Therefore, epigenetic modifications are specific to certain tissue and cell types. Don’t worry this was already done for you way back after fertilization and increasingly and increasingly throughout development until you got the parts you have now- you won’t be growing fingernails in your eye anytime soon.
Sadly though, epigenetic regulation is just one of the many things we slowly lose as we get older. Epigenetic marks are passed on to your body cells after they divide, but as we get older our cells forget where to place those methyl groups (C’s right?) and we forget the code (wait, acetylate that 9th lysine or methylate it?) and our methodical, highly regulated system of allowing certain genes to be ‘on’ and certain ones to be ‘off’ gets all jumbled up. In fact, as we get older our epigenomes begin to look a lot like the epigenomes of cancer cells. Depressing, I know.
Anyways, kittens always cheer people up, so let’s talk about how the calico cat got its spots. This can be explained by another epigenetic phenomenon called X-inactivation. Since females are XX and males are XY, females epigenetically inactivate one of their X’s so that there is balance between male and female genomes. X-inactivation is a girl’s way of leveling off the playing field with the guys. The reason there’s no such thing as Y-inactivation is because guys only have one, and they need it to be men and like sports and beer. In early development (we’re talking embryo) both of the X’s are active in females, but after a few rounds of cell replication and division, one of the X’s is randomly inactivated by turning almost completely into heterochromatin. All of the cells subsequently derived from a particular cell will retain that same pattern of X-inactivation. This concept can be demonstrated in the calico cat- which is always female. There are two alleles (versions of a gene) for coat colour in this cat. The gene for orange fur colour is located on one of the X chromosomes and the gene for black fur colour is located on the other X chromosome. The pattern of black and orange patches depends on which X was inactivated in the cells making the fur. For example, a black patch will form from all of the cells derived from the cell that had the X with the orange allele inactivated, and an orange patch will form from cells derived from the cell that had the X with the black allele inactivated. And it’s totally random- you could not find two calico cats with the same pattern of black and orange even if there genomes were identical.
So now that you know a bit about what your epigenome does for you, you probably want to know what you can do for it. The key to this is that epigenetic marks are reversible in a way that the sequence of your DNA is not (3, 6). This fact has been exploited in certain cancer chemotherapies that target either the enzymes that methylate DNA or the enzymes that tinker with the histone code (7). More promising though, is that knowledge about our epigenome has led to ways in which we can help prevent diseases such as cancer. We now know that things like smoking, exposure to certain toxins, diet in pregnant women and consumption of certain foods and drinks throughout a person’s life, all affect the epigenome in one way or another (3, 6, 8). And it’s not all bad news. For example, the active components in green tea have been shown in many animal models to protect against methylation going awry and in some places green tea is a highly prescribed chemopreventative agent (9, 10). Experiments in mice have led to guidelines about what kinds of food and in what quantities pregnant women should consume for optimal functioning of the child’s epigenome (6). And while smoking is still bad for you (making your epigenome look more and more like cancer), the good news is that some (but not all) of this damage is reversible if you’d only just quit already (11, 12).
So if after reading this essay, you’re feeling like you want to do something nice for your epigenome, might I suggest sitting down with it, maybe talk to it a little over a cup of green tea and promise it you’ll quit smoking.
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