The Trouble with Epigenetics (Part 1)

“You keep using that word. I do not think it means what you think it means”. The insightful Inigo Montoya.

Epigenetics is a word that seems to have caught the public imagination. This is especially true among those, both in science and without, who decry what they see as genetic determinism or at least an overly “genocentric” point of view. Our genes are not our fate, because epigenetics! Such-and-such disorder is not really genetic, because epigenetics! Acquired characteristics can be inherited, because epigenetics!

The trouble with epigenetics is that the word means very different things in different contexts. Each of them may be quite valid, but when these meanings are conflated or when the intended meaning is not specified, the word becomes dangerously ambiguous. This is especially evident in the fields of behavioural and psychiatric research where the term is much abused, often, it seems to me, to give an air of mechanistic truthiness to ideas that are in reality both speculative and vague.

Originally coined by Conrad Waddington in his famous “epigenetic landscape”, the word signified the emergence of the eventual phenotype of an organism through the processes of development, starting from a particular genetic profile. It was derived from Aristotle’s term “epigenesis”, which means pretty much the same thing – that organisms emerge through a program of development, as opposed to the theory of preformationism (where a teeny organism is already formed inside an egg and simply grows). Waddington’s new term incorporated the idea of a genetic profile, which shapes the metaphorical landscape over which each individual developing organism travels, channeling them with greater or lesser probability toward certain outcomes. The epigenetic landscape was intended to show that the relationship between genotype and phenotype is non-linear and probabilistic, not deterministic. This importantly incorporates effects of chance or the environment on the eventual outcome.

A newer definition arose with the growth of molecular biology. Here, epigenetics refers to mechanisms of gene regulation that determine the state of a cell and that are heritable through cell divisions but that do not involve changes in DNA sequence. Essentially, this means all the processes that make one cell of an organism different from another, that keep it that way and that allow that state to be passed on to that cell’s descendants. It is often more specifically used to refer to chemical modifications (such as methylation or acetylation) of DNA or of the histone proteins associated with it in chromatin. These epigenetic marks can affect gene expression and can be stably inherited from one cell to another (i.e., through mitotic cell division).

This molecular biology definition has really only a loose relationship to Waddington’s usage. It is obviously true that molecular mechanisms of gene regulation effect (as in mediate) the development of an organism. That is what cellular differentiation and coordinated organismal development entail. Genes are turned on, genes are turned off. Epigenetic mechanisms make the profiles of gene expression that define a particular cell type more stable, with different sets of genes held in active or inactive chromatin conformations. These two usages thus relate to very different levels – one refers to the profile of gene expression of individual cell types and the other to the emergence of the phenotype of the organism.

Now, clearly, the phenotype of an organism depends largely (though by no means completely) on the profile of gene expression of its constituent cells. And there are indeed a number of examples where the behavioural phenotype of an organism has been linked to the epigenetic state of particular genes in cells in particular brain regions. Importantly, such mechanisms may provide one means whereby environmental factors or particular experiences can have long-lasting effects on an organism, by changing patterns of gene expression in particular cells in a stable manner.

This has been demonstrated so far mainly in rodents, but in several different instances (reviewed here and here). These include responses to maternal care, to various kinds of stressors, including that caused by early maternal separation and to other experiences, notably drug exposure. In all of these instances, some environmental trigger or experience induces a response in an animal. One aspect of this response is to alter the set point of the system so that its response to subsequent events of the same type is changed (i.e., learning). In some cases, this involves changes in gene expression and epigenetic marks may help make such changes long-lasting.

The examples above include several where pathways have been worked out in detail, which lead from detection of some stimulus to changes in the chromatin state of specific genes, which are involved in setting the responsiveness or gain of the system. (As in the adjacent figure, from Caldji et al., 2011, showing effects on methylation of the glucocorticoid receptor gene). These may well represent important mechanisms of biological memory for regulating reactivity of various brain systems, which thus influence subsequent behaviour in a long-lasting fashion.

Based on these kinds of examples, epigenetics has become quite a buzz-word in the fields of psychiatric and behavioural genetics, as if it provides a general molecular mechanism for all the non-genetic factors that influence an individual’s phenotype.

Twin studies looking at the heritability of psychiatric disorders or behavioural traits show a consistent pattern: monozygotic twins are considerably more similar to each other for these phenotypes than are dizygotic twins, but are usually not completely identical. This demonstrates an effect of shared genes on phenotypic resemblance (i.e., heritability) but also highlights the limits of that effect – even genetically identical individuals are not phenotypically identical. Some other, non-genetic factors must be contributing to the phenotype of an individual and making monozygotic twins less similar to each other. But does “non-genetic” necessarily mean “epigenetic”?

The fact that environmental factors or extreme experiences can influence an organism’s phenotype is not news. In specific cases like those described above, the effects of such factors may indeed be mediated by molecular epigenetic mechanisms. But here’s the important thing – even though epigenetic mechanisms may be involved in maintaining some stable traits over the lifetime of the animal, they are just that: mechanisms. Not causes. Epigenetics is not a source of variance, it is part of the mechanism whereby certain environmental factors or experiences have their effects. Furthermore, these few examples do not imply that this mechanism is involved in mediating the effects of non-genetic sources of variance more generally.

Differences in the outcome of neural development can and do arise because the cellular events controlling cell migration, axon guidance, synapse formation and other developmental processes are inherently probabilistic. They are determined by the interactions of thousands of different gene products and affected by intrinsic noise at the levels of gene expression and molecular interactions between proteins. The outcome is never the same twice. This is epigenetics in Waddington’s usage – the emergence of a unique organism from a not necessarily unique starting point (the genotype). There is no reason to think epigenetic mechanisms of chromatin regulation are involved in these kinds of differences in neural circuitry.

Note that there are plenty of examples where mutations affecting proteins that mediate or regulate chromatin states (such as MeCP2, CHD7, CHD8 and many others) cause neurodevelopmental disorders such as intellectual disability, Rett syndrome and autism. But these are genetic effects, which disrupt the epigenetic molecular machinery. That is, the important difference between people in these instances is a good, old-fashioned DNA mutation.

So, while epigenetic mechanisms may indeed play a role in the stable expression of certain behavioural tendencies (at least in rodents), it remains unclear how general this phenomenon is. In any case, there is no reason to think of “epigenetics” as a source or cause of phenotypic variance at the level of the organism. And here is a plea: if you are tempted to use the term epigenetic, make it clear which meaning you intend. If you simply mean non-genetic, there is a more precise term for this: non-genetic.

In part 2, I consider a more egregious trend emerging in the literature of late – the idea that transgenerational epigenetic inheritance can provide a mechanism of heredity that explains the so-called “missing heritability” of psychiatric disorders. (It can’t).