Host: Nick Howe

2019 is Nature’s 150th birthday. To mark this anniversary, Nature is publishing a series of reviews that take a look at the past, present and future of science. The review I’m looking at today is about the field of epigenetics, so to start, I should probably tell you what that is. Epigenetics is, well, it’s actually quite hard to define.

Giacomo Cavalli

This is something which has been debated for decades, in fact.

Edith Heard

Epigenetics is a word that’s been used and abused, in my opinion.

Host: Nick Howe

This is Giacomo Cavalli and Edith Heard. They’re epigeneticists and the authors of the review paper. To help us better understand what exactly epigenetics is, it’s worth pausing to consider the history. It starts in the 1940s.

1940s music

Host: Nick Howe

It’s 1942 and biologist Conrad Waddington first coins the term epigenetics. He wants to unite the two fields of development and genetics.

Edith Heard

His definition was to try and link genotype to phenotype and try to understand how, through development, one builds up a complex organism but based on the hereditary material, so how to bring in the concept of the genes to actually explain how you go from simplicity to complexity during embryogenesis.

Host: Nick Howe

Waddington was trying to understand how, given that all cells have the same genetic code, they’re able to become different tissues in the body. After Waddington, there were tweaks to how the term epigenetics was used, but the next big step was in the 1980s.

1980s music

Host: Nick Howe

This was when DNA methylation – the addition of methyl groups to the chemical structure of DNA – was discovered to be involved.

Edith Heard

Scientists, so, in particular Robin Holliday and Art Riggs, came up with a hypothesis of cellular memory that would be based on DNA methylation, and this again was to try and describe how once a cell has taken on a identity, how does it maintain that identity through cell divisions, how does it not change its mind, and they actually used the word epigenetics to describe this phenomenon. So, they added this concept of memory to the notion of epigenetics.

Host: Nick Howe

The idea was that using DNA methylation, cells could remember what type of cell they should be – which gene should be on and which gene should be off in that cell type.

Edith Heard

What’s happened more recently is that epigenetics is now used to describe anything that goes beyond DNA. So, when you read the papers or the newspapers, you can talk about or read about epigenetics as being beyond genetics, beyond DNA, and anything that links gene expression to the environment. So, it’s become a very sort of vast area based on the different definitions that have been given, but when you talk to a scientist like myself, I have a more narrow definition. So, my definition of epigenetics was any change that affects gene expression and that can be heritable through cell divisions and yet can be reversible and doesn’t change the DNA sequence.

Host: Nick Howe

For now, at least, epigenetics refers to everything that affects how genes are regulated and which can be passed on from cell to cell. So, how does it work? Well, as Edith suggested, it’s quite a broad field, so the answer is that It works in a whole variety of ways. One common mechanism is by changing how DNA is packaged. Usually, DNA in the nucleus is packaged up with proteins called histones. The number and structure of these histones can influence whether a particular gene gets turned on or off. Another way is through the binding of transcription factors. These are proteins that bind to DNA to promote gene activation. But it’s not just about changing which genes are on or off. A key element is that these mechanisms are all heritable – they get passed on through cell divisions. This might be surprising. You’d think when DNA is replicated by being unwound and fed through enzymes that everything would be stripped away and reset, but it appears that a lot of DNA modifications are maintained and duplicated. How isn’t exactly clear. Epigeneticists are just starting to get a grasp, but it’s likely there are multiple mechanisms. Here’s Giacomo to explain.

Giacomo Cavalli

One possibility is that DNA-binding factors that are responsible for a given state will themselves always stay bound and in some cases, it has been shown that some transcription factors can stay there and actually that has been called bookmarking. So, even if a given transcription factor is not transcribing during mitosis, it stays bound there and then as soon as the cell cycle restarts, it will restart transcription.

Host: Nick Howe

Another way that DNA changes get passed down is through histones, which have their own epigenetic alterations that they can carry through cell division. Once the DNA has been replicated, these histone alteration marks will allow different factors that promote or supress the activity of genes to bind back, like they were in the old cell.

Giacomo Cavalli

So, there are several mechanisms and actually, epigenetics is about the possibility of having several mechanisms that frequently cooperate to obtain a very stable state that can be maintained.

Host: Nick Howe

But whilst these epigenetic states are stable and pass through cell generations, another characteristic of epigenetics is that the states are also reversible.

Giacomo Cavalli

So, epigenetics components are actually very interesting in that respect because they can maintain stability but at the same time, they are receptive to what’s happening around, so if you have any environmental change or if you have a stress or if you have a conflicting signal, they can interpret the signal and then change the state.

Host: Nick Howe

So, epigenetic markers are responsive to the environment. That maybe very useful for an organism adapting to a new situation, but the responses are quite narrow. Certain epigenetic markers will only respond to certain signals – say, a change in temperature or a specific chemical. Now, that’s important to emphasise because epigenetics has had a reasonable amount of hype around it, and one of the reasons has been this idea that things in your environment can affect how your genes are regulated. Whilst that is true, you can’t exactly change epigenetic profile by standing out in the cold or eating a salad once in a while.

Giacomo Cavalli

It’s the same as when people say DNA is the book of life and so what we are depends on DNA and once we will be able to read the DNA sequence well, then I will tell you who you are. This is certainly an exaggerated statement. At the same time, when you say that thanks to epigenetics we are free and we can decide who we will become, depending on diet, on lifestyle, we can be super healthy because of epigenetics – that’s also exaggerated.

Host: Nick Howe

The other thing that’s contributed to some of the hype around epigenetics is that in some cases, it appears that the markers may not only go from cell to cell, but also between parents and offspring. This has led to some people suggesting that what happens to you may affect your grandchildren. This transgenerational inheritance has been proposed in some organisms, including lab favourites like Arabidopsis, C. elegans and Drosophila, but it’s not well understood. It’s often hard to prove that any given effect across generations is down to epigenetics and not changes in the DNA itself. Here’s Edith again.

Edith Heard

Particularly in mammals and in humans, there was a period where a lot of so-called ‘epimutations’ were proposed to be transmitted from one generation to the next or to be induced in one generation and transmitted to the next and, in fact, until you’ve really looked at the genome and define that there hasn’t been a genetic change, I think it’s very preliminary and very dangerous. And in fact, in mammals, there probably isn’t that much that can be transmitted. There’s a reprogramming, as we put it, a tabula rasa, that happens in the germline to remove the epigenetic memory, the baggage of our past, and means that our genomes can come into a new generation to the fertilised egg without that baggage.

Interviewer: Nick Howe

But that’s not to say nothing is transmitted transgenerationally.

Interviewee: Edith Heard

There are a few sequences in the genome that probably can carry some epigenetic memory even across generations and those are what we call repetitive elements. Some of them, the youngest ones, the most mobile of them, might somehow avoid the reprogramming that we see in the germline and carry some of their epigenetic suppression right through into the next generation, so we think even in mammals there is some degree of epigenetic memory.

Interviewer: Nick Howe

Even then, it’s probably a stretch to say what we do in our lifetimes may affect our children’s or our grandchildren’s gene expression. Both Edith and Giacomo caution against such interpretations. Instead, they’re excited about the role that epigenetics has been shown to play, especially in disease.

Interviewee: Edith Heard

In diseases like cancer, epigenetic modifiers really matter. For me, this was a real eye opener. When you look at cancer genomes, many of the genes that have been found now to be disrupted and to potentially affect cancer, even drive tumour regenesis are epigenetic modifiers.

Interviewer: Nick Howe

Looking forward, both Edith and Giacomo are excited about the future of epigenetic research. Epigenetics appears to be involved in ageing, metabolism and a range of diseases. We’re also starting to get a better idea of what the role of the environment is in epigenetics, but there’s still a lot we don’t know.

Interviewee: Giacomo Cavalli

We know relatively little, in terms of real life, so how much of a phenotype of an organism really depends on the sequence of the DNA versus epigenetics, so I think it’s a very exciting time ahead.