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An evolutionary battle of the sexes: The epigenetic phenomenon of genomic imprinting

In the late 19^th and early 20^th century, scientists were looking for the chemical that allowed organisms to pass their traits on to their progeny, and also allowed cells in the body to pass on their specialised function as they divided to create new cells. It was thought that this must occur via proteins, as these vary between different cell types and are intricate and abundant enough to contain complex instructions. However, to the shock (and disbelief) of many, it was instead found that heritable information was transmitted via DNA, and that the DNA sequence was the same in every cell across the whole organism.

How could such diversity in function be maintained between an intestinal cell, which extracts nutrients from the gut, and a neuron, which relays information via electrical impulse, when they are built using the same information? How can cells remember their identity when what is passed on is the same across all cell types? The answer lies in which parts of the DNA template are utilised, or ‘read’, by the genomic machinery and which parts are ignored.

Understanding how cell fate is established

Investigation of how cell fate decisions are made is at the heart of modern biology. Knowledge of these decisions opens up the possibility of manipulating them to serve our needs, in both medical and industrial applications. Imagine if we could induce cells from a patient to become healthy neurons, replacing diseased ones, if we could manipulate bioreactors or crops to produce useful chemicals and food more efficiently than ever before, or if we could reverse any loss of cell identity as we age.

Finding the answers in epigenetics

But where do we start? The earlier biologists had a point, it is hard to conceive of a way fate memory can be maintained through DNA if you think of it in terms of sequence alone. In addition, traits have been observed to be heritable that cannot be due to the DNA sequence. The study of these traits and how they come about is termed ‘epigenetics’ with epi being the Greek prefix for ‘over’, or ‘around’. Epigenetics encompasses several different chemical modifications to our DNA that can affect which genes are accessible for ‘reading’. DNA methylation is one such chemical modification to the DNA. It is in part through such processes that cell fate is thought to be established and maintained, and failure in epigenetic processes is one of the causes of human and animal disease.

The phenomenon of genomic imprinting

The most well characterised and established epigenetic phenomena occurs through a process termed genomic imprinting. As diploid organisms, humans have two copies of each gene in their genome, one inherited from each of their biological parents (with the exception of genes on the X and Y chromosomes) and both are usually active. Importantly, it has long been observed that one copy from each parent is required for mammals to develop normally, with two copies of a gene from one parent not being sufficient to support normal development.

However, in some instances, only the copy inherited from one of the parents is active and this phenomenon is known as genomic imprinting. The parent origin of the inherited DNA therefore influences traits in the offspring. Imprinted genes have parent-specific DNA methylation marks that are established in the egg or sperm cell. The result of these marks is one parental copy of a gene is switched off, and typically this persists throughout the individual’s lifespan. 

Correct imprinting to control gene expression is important for normal development. Errors in this process cause a range of imprinting disorders, such as Prader-Willi and Angelman syndromes, caused by deletions on the paternal (in Prader-Willi syndrome) or maternal (in Angelman syndrome) copy of chromosome 15. Molar pregnancies (where embryonic and placental tissue does not differentiate and develop in a manner compatible with a viable offspring) and a broad range of other imprinting disorders have also been observed when correct DNA methylation does not occur at imprinting regions. Understanding the mechanisms of how these diseases occur is an important first step in their treatment and prevention.

In 1991, Denise Barlow identified the first imprinted gene in mice; Igf2r. Since then, hundreds of other imprinted genes have been identified, most of which have conserved expression patterns among mammals. The high degree of conservation between mouse and human imprinted regions makes the mouse a useful model system in which to study the underlying mechanisms of imprinting disorders in humans. In addition, understanding the rules that govern how imprinting can be established and maintained has shaped our conception of other epigenetic phenomena important for health and disease, and further study of its mechanisms may lead new insights that can be applied beyond the specific parts of DNA that are subject to it.

Our research

At the Institute, our research aims to elucidate the underlying mechanisms of DNA methylation establishment and maintenance in the germ cell and developing embryo, shedding light on both its interaction with cell fate decisions and mechanisms such as imprinting. This will inform approaches by which epigenetics can be manipulated in cells and organisms, potentially leading to applications in regenerative medicine, healthy ageing, and improved assisted reproduction technology.