Janus in our genes: a brief introduction to epigenetics. In 1650 the term ‘epigenesis’ was coined by William Harvey to describe the increase in complexity from embryo to adult. After Darwin’s vindication, the paradigm of the gene as the unit of selection came to dominate biology. But how genes acted to result in fully formed organisms remained a mystery. Why did fish, mammal, and reptile embryos all look similar to begin with before differentiating into distinct morphologies?
‘Epigenetics’ was first used in 1942 by Conrad Waddington to describe the different routes of development. He pictured an epigenetic landscape of bifurcating valleys and hills determined by differential regulation of genes. The bacterial operon, discovered in 1961, was the first gene regulation mechanism to fit this concept. Subsequent research in developmental biology in the 1960s uncovered the malleability of chromatin, the way DNA is densely packed into cells, and other potential mechanisms controlling development in higher organisms.
The importance of finer detailed mechanisms like histone protein modifications and DNA methylation was realised independently, before being united under the term ‘epigenetics’ in the 1990s. However, even then the definition of epigenetics was nebulous and subjective. Arthur Riggs, from the Beckman Research Institute, proposed in 1996 the definition as: “The study of mitotically and meiotically heritable changes in gene function that cannot be explained by changes in DNA sequences.” Meaning changes in gene regulation or control that are preserved as a parent cell divides into two daughter cells, either in the somatic body, or as a germline gamete. This was followed in 2007 by Adrian Bird of Edinburgh University taking into account research into large scale structural conformation of DNA with: “The structural adaptation of chromosomal regions so as to register, signal, or perpetuate altered activity states.”
Epigenetics as we know it today. Today, we understand epigenetics as a collection of mechanisms that alter gene transcription and regulation without altering the underlying genetic code. The same collection of genes can therefore be used in different combinations, a process instrumental to cell differentiation during development of higher organisms. These changes are often not permanent and confer a degree of adaptability to changing environments. And the fact that some epigenetic modifications aquired during the life of an organism can be transmitted between generations revives a cautiously Lamarckian paradigm.
DNA methylation is the most widely studied and understood mechanism, influencing how DNA is wrapped around histone proteins and therefore how it can be presented to transcriptional mediators. Other epigenetic mechanisms include the methylation and acetylation of histones, methylation of RNA, and non-coding RNAs.
Epigenetics in other domains of life. In bacteria, DNA methylation is thought to have evolved to aid a protective mechanism against phage virus attack. Restriction enzymes that digest DNA selectively degrade non-methylated DNA from invading viruses, whereas DNA with a methyl group attached to adenine is not degraded. In archaea, the other domain of life without an organised nucleus, some species wrap their DNA tightly around histones, just like we eukaryotes do. However, archaeal histones lack the structures necessary for many of our acetylation based epigenetic modifications.
Although enzymatic mechanisms are thought to be similar across the board, increasing complexity in eukaryotes from yeasts and human beings is associated with more and more complex combinations of histone modification. In higher eukaryotes, epigenetic modifications to DNA are dominated by methylated cytosine (5mC), at sites where it precedes a guanine (CpG). This is mediated by methyltransferase enzymes like DNMT-1 in humans. Measuring methylation patterns has been a key driver in the growing field of epigenetics, as changing methylation patterns result in complex interactions that can ultimately alter gene regulation.
So, are we our genes? Aside from helping to orchestrate the growth and assembly of trillions of cells into one cohesive organism, epigenetic changes confer a degree of phenotypic flexibility beyond, and, crucially, faster, than what is possible by natural selection. This also means that epigenetic changes that throw off the normal regulation of bodily functions can cause illness and diseases. In particular, epigenetic misregulation of the immune system and cell cycle is implicated in, or at least strongly associated, with a wide range of autoimmune diseases and cancers.
The past two decades have seen a surge in epigenetics research and publications, especially as its relevance to clinical studies, and preventative healthcare is being realized. Therapies are beginning to make it through the trials pipeline for drugs aiming to reprogram faulty epigenetics in cancer, for example by targeting acetylation of histones or inhibiting DNA methylation. But the complexity of epigenetic gene regulation means the first step to managing chronic dysregulation of the epigenome is being aware of and monitoring those changes in the first place. So, are we our genes? Of course, but they are just the beginning of the story.
Toby Call is a co-founder at Chronomics.
