The Epigenetics Revolution

Mapping the human genome was a gargantuan task. Identifying and analyzing all of the genes that make up a human being is no small feat, even for a team of dedicated experts – so it's no surprise that the project’s completion led to wild fanfare and public enthusiasm.

Bill Clinton, who was president when the genome was first fully sequenced, went on record to say, “Today we are learning the language in which God created life.” The UK Science Minister, Lord Sainsbury, declared, “We now have the possibility of achieving all we ever hoped for from medicine.” Big statements, from powerful men – but in hindsight, were they all that accurate? Well, perhaps not entirely.

Part of the problem was that we overestimated the importance of DNA. We thought of it as a huge set of strict biological instructions, like a mold for making identical parts in a factory. But as it turns out, the reality is really quite different.

You see, we might be better off thinking of human DNA as a script rather than a mold. Let’s consider an actual theater script for a minute. Take Shakespeare’s Romeo and Juliet, for example – although every production takes Shakespeare’s words and stage directions as their starting point, each performance ends up different, because the script can be interpreted in so many different ways.

During rehearsals, the director and actors will scribble their own notes and instructions in the margins of their starting scripts – and in doing so, they turn the initial work into something new and idiosyncratic.

So, what does that have to do with biology? Well, if we think of living things as theatrical productions, then DNA is the first script we’re given to work with – our original masterpiece. Add in those all-important jottings in the margins that make each script unique? Well, that’s epigenetics.

Epigenetics controls the expression of our genes – directing the extent to which any one gene carries out its function. Epigenetic modifications are like the actor’s little notes saying, “Speak these words quietly,” or “Shout this bit,” or even “Skip this line entirely.”

In other words, they’re the unique instructions that tell the individual cells that make up your body how to behave in different circumstances. Epigenetic information is what stops a skin cell from turning into a neuron, or a liver cell from turning into skeletal muscle.

Just as Shakespeare’s play can give rise to both traditional performances in Renaissance style, and modern interpretations like Baz Luhrmann’s 1996 film, so too can a single “script” of DNA give rise to very different characteristics.

To understand this a bit more, let’s forget about Romeo and Juliet for a minute, and focus on a less appealing topic: mice – inbred lab mice, to be exact.

Now, these mice aren’t inbred through any fault of their own. Their human handlers have bred them selectively with their siblings generation after generation, to the point that they have become genetically identical. And yet, despite each mouse seeming identical to its siblings at birth, as the mice babies grow, they begin to show their differences – in things like their body weight and temperament, for example. And this is despite being kept in exactly the same environment. 

This difference between genetic makeup, known as genotype, and real-life traits like weight gain, known as phenotype, is often explained by epigenetics. So let’s slow things down a minute and take a look at what that actually means for our mice. 

In terms of mechanics, the expression of their genes is modified in two main ways.

The first is through what’s called DNA methylation. That’s when a chemical tag called a methyl group is added to DNA. Most of the time, this specific process results in genes being switched off.

The second type of epigenetic modification involves changes to histones, a type of protein that structures DNA in the nucleus. Changes to histone proteins can be more varied: instead of just turning a gene off, they can act like a dimmer switch, strengthening or weakening the expression of a gene in the same way you’d turn your house lights up or down.

For our young mice, where we see differences in weight, it’s thought this is caused by both DNA methylation and histone modifications. And it’s likely that these epigenetic differences are established very early on – maybe even in the womb.

If we return to our Shakespearean analogy, we can look at DNA methylation and histone modifications as a kind of shorthand that actors use to alter their scripts. DNA methylation says, “Omit this,” while histone modifications tell an actor how loudly and intensely they should deliver certain lines.

Now that we know what epigenetics is, and how it works, let’s look at some of its ramifications for humans. After all, it’s not just inbred mice that are affected!