Okay. So now we're going to talk about histone protein modification. So just in case you need a refresher, what are histone proteins? Do you remember where they are? Right, they are in the nucleosome, and that is what the DNA is wrapped around to be able to package. So histone protein modifications can affect how tightly DNA is packaged, and remember, we already said that if DNA is packaged too tightly, gene expression won't occur. So this definitely regulates gene expression.
So, how are histone proteins modified? Well, histone proteins actually have tails, they have these little protein tails that hang off of them, and they contain a bunch of different amino acids, but the two important ones are lysines and arginines. And these 2 amino acids can be modified through a bunch of different ways, most of which we're not talking about, but the two most important ones are through the addition of methyl or acetyl groups.
So, let's talk about acetylation first. Acetylation of the acetyl groups results in open chromatin. So this is what you need to know, you need to be able to connect acetylation with open chromatin, and if the chromatin is open, what does that mean for transcription? Is that going to activate it or suppress it? Right. It's going to activate or promote transcription. Now acetylation is reversible, and there are enzymes called histone deacetylases that come in, can remove that acetyl group. When the acetyl group is gone, what is that going to do with the chromatin? It's going to close it back up again and repress transcription. So you have an acetyl group there, a bunch of acetyl groups there, that open this region of the chromosome, it's going to promote that transcription of those genes present there. If the acetyl group is not there, it can be closed, and if it's closed, that means that transcription of those genes won't occur. Obvious gene regulation.
So the second type is methylation, this is the process of adding methyl groups. Now, most often, methylation causes closed chromatin but notice I said most often because occasionally it can support open chromatin. But this is where it gets confusing, because some professors want you to just sort of know for the test, acetylation causes open, methylation causes closed. So I suggest that before you get to a major test, that you go to your professor and say, hey, does methylation occasionally cause open chromatin, and what is the answer you're looking for on the test? Because some professors want you to know that there is this, you know, most of the time it causes closed, but can cause open. And some of the professors just say, let's make it easy for them. Acetylation causes open, methylation causes closed. So make sure you know what your professor wants you to believe that methylation does, before you get to a test. So, methylation often causes closed chromatin. Now, methylation when it's on there, what it does, like the functionality of how this is going to activate or suppress transcription, is when there's a methyl group there that creates a binding site. So other proteins can bind to that methyl group, and then proteins come in and they can either activate or suppress transcription depending on the proteins that are binding to that area. Now obviously, there's a bunch of different amino acids. It's not just 1 lysine, and it's not just 1 arginine. Histones are made up of a ton of amino acids, and there's a bunch of histone proteins in the nucleosome, each one of them have tails, so there's all these huge combinations, which we refer to as the histone code. Now they, so it's the combination of all the histone modifications that affect gene regulation. And I only talked about methylation and acetylation, but there's actually over a 150 different types of modifications that can occur on a histone protein, amino acid, and then on top of that, there's multiple amino acids. So this, this code is huge, and we haven't broken it yet. We don't know how to read it yet. And so, what kind of what signals cause activation and what signals cause suppression is not at all well understood. But there is one pattern that we can say for certain that we know, and that's the pattern of CpG islands. So most CG dinucleotides, and dinucleotide just means we're referring to 2 nucleotides here, cytosine and guanine. So, in the genome, the majority of these are actually methylated. Sorry if you can hear that siren that's outside. But anyways, most of these are, methylated. So throughout the entire genome, if you have a pair of cytosine and guanine, the majority, like, overwhelming majority, you're going to be methylated. But there are regions of unmethylated cytosine and guanine dinucleotides, and we call these CpG islands. So regions where cytosine and guanine are not methylated. And they are not, when they are not methylated, they are very often found in promoter regions, which makes sense because promoters need to be able to activate genes. So you don't want this methylation occurring in a promoter because that could really cause a closed chromatin and result in the suppression of the gene that the cell may want to actually activate. So here's an example. So here is the nucleosome, and each one of these is a type of histone protein, and you can see that they have these tails on them. Some of them have 1, some of them have 2. And as you go along here, you can get all different types of combinations. Right? You can get, like, this is a lysine here with acetylation and methylation on it. You have a lysine up here with just acetylation. You have a ton of lysines and arginines up here with just acetylation. You have things I didn't talk about including phosphorylation, the one I don't really know much about, the ubiquitination that occurred occur on here. And so all of this, all this whole combination here means something. This is going to say, okay, activate this gene or suppress it. Right? But we don't know just by looking at this whether or not this gene would be activated or suppressed, we would have to actually do an experiment to determine that. And so this histone code is a code that scientists are currently working on trying to figure out, but you can say it's extremely complex, and, obviously it's not going to be easy to figure out. So with that, let's quickly get to the 3rd form, and that is actually the histone variants. Variants. So histone proteins are generally very well conserved. The same histoproteins throughout pretty much every organism, every eukaryotic organism, even further than that. And, histone variants are very rare, and what they are is just like their variants. Right? They're histone proteins, but they're not quite the same as the universal histone proteins that are used. But, generally, they're found in unique chromosomal regions. So an example of this is the centromere, which is always very tightly, I mean, just like extremely tightly packaged heterochromatic, contains its own H3 histone protein variant. So H3 is just a type of histone protein, and there's a special one found at the centromere. Why is it there? No one really knows, but people suspect that it has something to do with the centromere. It has this, you know, very tightly, just like abnormally tightly packaged DNA, and that that histone variant may play a role in that. We don't know for sure, but that's just kind of the idea. So histone variants are the third way that gene regulation can be controlled, because the centromere, obviously, nothing in the centromere location is getting transcribed, and that could be potentially due to this histone variant. So with that, let's now move on.
