Sokolowski - biological mechanisms of epigenetics

We used to say it’s about DNA methylation, adding a chemical mark to the DNA sequence, which changes the expression of the gene or the gene product that’s made. But now we know that epigenetic comprises a lot of different biological mechanisms that affect how much of the transcript, that’s the RNA transcript, or how much of the protein is going to be involved in any given process. 

The epigenetic mechanisms that are studied, that is studied the most in mammals is CpG DNA methylation. And it puts a mark on the DNA sequence and that mark is a little methyl tag, a little chemical tag. And depending on where that mark ends up, if it’s near the start of a gene it can turn down-the way you use a dimmer switch in lighting-it can turn down the expression of that gene; it can turn down how much RNA the gene makes. And so it’s been classically studied from the perspective of people who have a lot of stress or trauma. And genes involved in coping with stress like the genes involved in the glucocorticoid pathway are looked at and there’s methylation marks that end up in the promoter of the glucocorticoid gene which turns down the amount of transcripts or RNA made, which has later consequences for how we cope with stress, our immune system and our health and longevity. 

That’s only one type of epigenetics, and there’s other types of epigenetics that are important and have been studied more and more in the last few years. And from an update perspective one of those types is called histone modifications and here you have always the DNA sequences wrapped around these proteins called histones. That’s now it normally lives, and those histones, the DNA is wrapped around and they’re all tightly together. 

I use the analogy of the DNA sequence being like a hair and the genes being beads on a string so now that DNA sequence has wrapped around these proteins and by that wrapping it all gets very, very much condensed and tight together. That’s how our chromosomes look under a microscope. We don’t see a full DNA sequence. 

So when that DNA sequence is very tightly wrapped it’s very hard for the genes involved to have their DNA transcribed into RNA. In other words gene expression is also turned down. And what happens is that the DNA is wrapped around these histones and now instead of the methyl or chemical tags going on the DNA sequence, as in DNA methylation, they’re added onto the histone tails. And here again depending on the type of tag you can have DNA expression turned down or turned up. The one that we study in my lab is a certain histone methyltransferase that represses gene expression. And just like with DNA methylation depending on where it lives, that mark, it can affect the expression of the gene. So it’s like DNA methylation, histone modification, but instead of modifying the DNA it’s modifying these histone tails that the DNA is wrapped around. 

It is important to know that when it comes to gene expression it’s not just one mark. There’s a landscape of different epigenetic modifiers sitting on that gene and near that gene. And depending on what that landscape is, the gene will either open itself to be transcribed to make RNA or it will close itself more tightly. And when it opens itself there’s something called transcription factors that come in to start the transcription of the DNA and those transcription factors are the things that are responsive to the environmental experience. And so when you have the DNA really tightly coiled there’s no room for those transcription factors to come in, bind the DNA right before the start site and make the RNA.  

The main point is that in the past we thought there was just one epigenetic modification, the DNA methylation. And now we know there’s many, all acting together on a gene with different environmental inputs affecting which ones go where and what the output will be from that gene. We also know that these DNA methyl marks are not only right next to the gene affecting gene expression but they’re also found in places we can’t really understand all over the genome and we don’t know what they’re doing but we want to understand that and that’s something for the future. 

The third kind of DNA of epigenetics is microRNA and they’re also starting to be studied and these are just tiny little RNA sequences that attach to any RNA that’s made and kind of sop it up so it can’t be used. So these little RNAs are affecting, making these gene products not at the level of the DNA to the RNA at the level of transcription, but at the level of what we call translation when the RNA gets made into a protein. 

And these microRNAs are particularly interesting because they target lots of different classes of genes. So one little mark of microRNA can reduce the expression of genes involved in sleep or cognition or stress responses or neglect for instance. So, they’re a way to study how a whole process might be modified epigenetically so that the genes are changed according to experience. So it could be how sleep deprivation influences cognition, that’s one of the things we study in my lab. Or if you have sleep deprivation some people need to catch up when they don’t get enough of a night’s sleep and other people are okay. And these kinds of things are affected by; regulated by lots of genes but there’s also these epigenetic modifiers like these microRNAs that are fine tuning the expression of lots of genes involved in that process. 

So those are the three things that are now mostly studied; the DNA methylation, there’s different types, some make the lights less on the dimmer switch, some turn up the lights, here the lights means expression. There’s histone modification which does much the same thing but it’s not on the DNA sequence, it’s on the histone tails, the little marks. And then there’s microRNAs that are being studied because they seem to be important, kind of acting in a hierarchy high up affecting lots of other genes. And there may be more that are still being discovered. So it’s not that DNA methylation as we thought was a mechanism for nurture, there’s many different epigenetic ways that our experience gets embedded in our biology and now we’re trying to understand that.