Our genes are the ultimate blueprint for who we are and how we look. They decide simple characteristics of our appearance like hair or eye colour as well as more complex traits such as height or even intelligence which no single gene encodes. These complex traits arise from the highly coordinated expression of multiple genes that work together in ensembles to produce the range of heights and appearances that we see in our population.

But what influences which genes are expressed in which cell, or how strong of an effect any given gene should be?   Despite having the same DNA in a neuron in your brain and in a white blood cell in your bloodstream, these two cells are vastly different in shape and function and use different, specialised subsets of genes that give them their unique cellular identities.  To achieve this, cells restrict or facilitate access to genes through chemical alterations to DNA that change its shape.

This is a process known as epigenetics, an additional layer of control over our DNA that chooses which parts of the genetic blueprint are used in different tissues of our body, thus guiding our development from embryos all the way into adulthood, a process from which epigenetics gets its name: epigenesis.

To understand epigenetics a knowledge of chromatin structure is needed.  You see, the DNA in the nucleus of a single cell isn’t free floating, but is instead wrapped around proteins called histones that bind along the length of DNA. Once DNA has bound to histones forming a nucleosome, many histones can bind to each other thus condensing the DNA into a small area.  Most of the DNA in our cells exists in this form, highly condensed unreadable chromatin, called heterochromatin.

Cells achieve subtle control over which genes are read, or how often, through the covalent modification of DNA and histones that alter its readability, these are called epigenetic markers and they come in two broad forms.

  1. DNA methylation on cytosine residues in the DNA. Methyl-cytosine binding proteins recognise this marker and promote the condensation of DNA into silent heterochromatin

  2. Histone modifications can take a variety of forms, most notably, histone acetylation reduces the charge attraction between histones and DNA favouring chromatin decondensing and active transcription.

Since epigenetics can influence every aspect of our biology by acting on our genes, learning the rules that govern where epigenetic markers are placed or how these precise markers are maintained could help us begin to answer some very long-standing questions in biology. Questions like why disease susceptibility increases with old age, why some people live to much older ages than others, or even potentially accelerate the adaptability of species to environmental change.

Curiously, the pattern of epigenetic markers on the genomes of identical twins can differ, despite having an identical genetic make-up. These differences become more pronounced with age, suggesting that the older identical twins get the less identical they are.

twins young
twins old

In twins, epigenetic markers decrease in similarity over time.
(Yellow = similar; red and green = dissimilar)
Fraga et. al. PNAS 2005

This phenomenon called epivariation (surprise surprise) can be driven by many factors such as random variation, mutation in the DNA sequence onto which epigenetic markers are placed or, most excitingly, environmental stimuli.  Now why is that exciting I hear you ask?

Well, genetic variation by mutation is a slow process that relies on the success of subsequent generations in the wild, something which is not likely considering that genetic mutation occurs in random locations on the genome and is therefore indifferent to the environmental pressures placed on an organism. Epivariation therefore offers a far faster way for an organism to adapt to changes in its environment and potentially pass these immediate benefits onto their offspring.  Transgenerational epigenetic inheritance, as it is known, excites the living shit out of me and epigeneticists alike as it suggests that the decisions we make about the environment in which we live can have some influence over the genetics of our descendants; not the DNA sequences they inherit but how they are used, thus blending nature and nurture into the same idea.

In 2014 an epigenetics study entitled “Parental olfactory experience influences behaviour and neural structure in subsequent generations” found that by providing an odor stimuli to mice (acetophenone, kind of like orange blossom I’m told) and then shortly afterwards giving them a mild electric shock they could cause the mice to freeze in response to the odor alone. Nothing surprising, right? The mice learn to associate the smell with the electric shock and then freeze in place when the smell arrives, just classical Pavlovian conditioning.  Well they next allowed the conditioned mice (F0) to rest for two weeks, then mate with unconditioned mice.  The offspring (F1) were then exposed to acetophenone but without any foot shock. They found that the offspring observed similar freezing behaviour to their parents, and significantly greater than the different control groups. Proving that it was odor specific, not a learned behaviour from the mice’s parents and that it required sexual transmission via gametes.  This behaviour was even transferable to the next generation (F2), even though neither F1 nor F2 were ever exposed to the odor prior to testing.

Spooky huh? Inheritance of a behavioural trait across 2 generations that needs only gametes to occur. Looking deeper into the possible cause of this phenomenon the researchers checked the methylation state of the gene which produces the specific smell-receptor for acetophenone. They found that the gene had significantly lower methylation than controls, indicating dis-inhibition of expression of this gene, and therefore greater sensitivity to the odor acetophenone. Additionally, the region of the brain to which this odor receptor sends signals was enlarged compared to controls.

The problem here is that this contradicts what we currently know about the process of embryogenesis.  After fertilisation of an egg by a sperm almost all the epigenetic marks on the genome are erased, and there is a widespread reduction in the amount of heterochromatin. This is essential since cells of the embryo must be totipotent – and have the ability to not only divide countless times but also differentiate into any tissue of the body, which means that all of the genome must be equally accessible. Yet somehow epigenetic marks acquired during the lifetime of the parent mice (F0), are transferred onto the genome of their sperm or eggs during their lifetime and then transmitted to their children (F1).  So experiences can cause the live-updating, if you will, of our epigenetic markers so that subsequent generations are better prepared for their environment.

So if the epigenetic markers are erased, how can they be transferred? Well current thinking is that RNAs, stably bound inside protein complexes can be transferred via gametes, and so even after the epigenetic markers are erased,  RNA complementary to the relevant DNA sequences – like an odor receptor for example – may guide the addition of epigenetic markers to the sequences which they bind.   It is important to note though, that while the role of RNAs in epigenetic silencing is already established, solid evidence for its role in transgenerational epigenetic inheritance in mammals hasn’t yet been found.

In any case, this has big implications for human health. Nutritional conditions during pregnancy are one of the most heavily investigated topics and though not truly transgenerational (as the baby is already conceived), these forms of inter-generational epigenetic modification do exist.

The thinking here is that poor nutritional conditions during pregnancy may influence metabolism and health of children far later in their lives, potentially adapting the embryo to an environment with low resources after birth. This so called “thrifty phenotype” has anecdotal evidence in humans. During the Dutch famine at the end of WWII, babies exposed to famine during gestation had a poorer glucose tolerance during their lives than those born the year before the famine. Studies have found babies born of famine exposed mothers had more stored fat, and this occurred even among the grandchildren of famine mothers.

As research into epigenetics continues to increase and we begin to understand the rules that govern the epigenetic modification of DNA we will be faced with new possibilities for fighting and preventing disease. If we discover that our self-imposed environment, diet or lifestyle can have prominent transgenerational effects then we will need to take better care of ourselves don’t you think?


Joe Sheppard
graduated in 2016 from the GTC Master’s program.

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