Read more: “Instant Expert 29: Epigenetics“
The extraordinary truth emerged in the 20th century that biological information is stored, read and replicated in the form of DNA. Our genes can be thought of as packets of information written in sequences of DNA bases, which encode proteins that perform the functions necessary for life.
The term “epigenetics” refers to a vast array of molecular mechanisms that affect the activity of genes. Epigenetic “switches” turn gene activity up or down. They have long-lasting effects that can persist through cell division, and sometimes through sexual reproduction too. The human genome project, ambitious as it was, has turned out to be only the start of the quest to understand the molecular blueprint for life. Our sights now turn to the epigenome
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First clues
In the 1950s a broad set of principles covering how the instructions for life are encoded and passed on between the generations began to emerge from nascent science of genetics. Yet inheritance did not always seem to follow the rules. For instance, the effects of a gene controlling seed colour in maize seemed to disappear sometimes, only to reappear in later generations. How could the influence of a gene come and go in this way?
Later in the same decade something similar turned up in animals, this time involving the sex chromosomes. In mammals, males have an X and a Y chromosome, while females have two copies of the X. To avoid females getting a double dose of X chromosome genes, one X chromosome is selected at random in each cell of the embryo and permanently shut down. The process of X chromosome inactivation happens early in fetal development and is stably transmitted through multiple cell divisions as the offspring grows.
This is nicely illustrated in female tortoiseshell cats, in which a gene that codes for fur colour resides on the X chromosome. Their distinctive patches of different-coloured fur come from patches of skin cells that have inactivated one X chromosome or the other.
A less obvious version of gene silencing, known as “imprinting”, was discovered a few years later. Genes are present in duplicate in each cell of the body – one from each of the two parents. Some genes, however, behave differently depending on which parent they come from.
A classic example is the gene for a signalling molecule called IGF2 or insulin-like growth factor 2, which promotes fetal growth. The IGF2 gene inherited from the father is switched on while the one from the mother is permanently turned off.
This imprinting seems to make sense from an evolutionary standpoint, as fathers have more interest than mothers in having big babies – the mother might do better conserving her resources for future children. But how could a gene “know” if it was inherited from mum or dad?
“Fathers may have more interest than mothers in having big babies – but how could a gene ‘know’ if it came from mum or dad?”
By the 1980s it was starting to be appreciated that these and other unusual findings conformed to a pattern and could in fact be aspects of the same phenomenon. Each involved persistent changes in gene activity that did not involve mutations in the DNA sequence itself.
The DNA is all there, but some of it is somehow stopped from carrying out its normal function by an influence that acts upon or above genetics, hence “epigenetics”.
Solving the mystery
We started to get the first glimpses of some of the mechanisms involved in epigenetic phenomena in the 1970s and 1980s. Most turned out to entail chemical changes to either DNA itself, or its packaging proteins. Some of these chemical marks or tags promote gene activity – that is, allow a gene’s protein to be manufactured – while others have the opposite effect, shutting a gene down.
The primary means of controlling gene activity is thought to be through transcription factors, proteins that bind to a stretch of DNA next to a gene, known as its control region, to turn it on or off. Epigenetic changes seem to complement the activity of transcription factors.
The first example discovered was DNA methylation, which involves a small chemical subunit called a methyl group being added to DNA. The “letters” of the DNA code were known to consist of four types of base: adenine, cytosine, guanine and thymine. We’d known for decades that DNA also contains small amounts of a fifth base, methylated cytosine but only in the late 1970s did it become possible to map where in the genome this modified base appeared.
A striking pattern emerged: DNA methylation is dotted around over most of the genome, but is usually conspicuously absent from gene control regions. Crucially, when the control region is methylated, the gene cannot be turned on and is said to be silenced.
Methylation of a gene’s control regions is used, for example, to silence one female X chromosome and to ensure that genes involved in the making of sperm and eggs are switched off in the rest of the body. Importantly, patterns of DNA methylation are copied when DNA is replicated and are therefore passed on from a mother cell to its daughters as the cell divides. This cell-to-cell heritability helps explain why epigenetic gene silencing is so stable over time.
What’s in a name?
Epigenetics is a young science and even the word’s meaning is up for debate. A common view is that it refers to heritable changes within a cell that do not involve changes to the DNA sequence. Emphasis on inheritance means that as well as chemical changes to DNA or its packaging proteins, this idea also embraces RNA sequences that switch genes on or off, and even transcription factors. Even heritable phenomena that have nothing to do with DNA would be covered, such as self-replicating prions.
An alternative definition focuses on the chemical changes to DNA and its packaging proteins, whether heritable or not.
Arguments about definitions are potentially endless. In the end, we need not care too much what these biological processes are called. What we really want to know is how these complex systems interact to affect the activity of the genome.