Sins of the mothers

Whether you turn out to be a good or bad mother is partly down to how you were treated by your own mother: at least if you are a rat.

Rats need their mothers to lick and groom them in the first week after they are born. If that doesn’t happen, it leads to poor outcomes in terms of how long the newborn rat can expect to live, its ability to cope with stressed conditions such as scarce food, and its ability to be a good mother themselves.

This is an example of a type of inheritance from one generation to the next that doesn’t lie simply in the genes and DNA sequences we receive from our parents. Instead, biological outcomes are decided by factors that affect which of our genes are active, rather than changes in the DNA itself.

This is called epigenetics: a research area that seeks to explain how genes are switched on and off, and how these controls are inherited, determined during development of the embryo, or affected by environmental factors.

‘Cancer is largely an epigenetic disease,’ says Professor Jane Mellor of the Department of Biochemistry. ‘The pattern of genes that are active in cancer cells can tell us a lot about how the cancer will progress. We find that tumour suppressor genes are often switched off and that tends to mean a poor prognosis for the patient.’

‘In agouti mice, the diet of the females can influence the coat colour of their pups through epigenetic changes,’ she adds. Agouti mice are named after their brown coats, which can vary from a pale yellow to a dark brown according to the level of one protein. ‘The diet of the mothers can also affect the birth weight, obesity, and disease susceptibility of the pups through changes acquired in the womb.’

There are two clear mechanisms that change which of our genes are active. One involves RNA. For example, women have two X chromosomes and one has to be switched off to avoid two copies of every gene on the X chromosome being used. This is done using an RNA molecule.

The other mechanism involves modifications to the chromosome itself. Chromosomes consist of a DNA molecule wrapped up around globular proteins called histones. The position of the histones on the DNA can change which genes are expressed, and there is a whole raft of chemical modifications that can be made to the histones that also determines which genes are active.‘

These different modifications are like little flags that show which genes are active and which are switched off,’ says Professor Mellor. ‘It’s a histone code that determines which gene products are made and when.’

‘This has led to the idea of an “epigenome” – much like the human genome – where we endeavour to map out all the modifications, where they are, in what tissues of the body, and at what time in development.’

‘The pattern differs over time and according to the environment we experience,’ she explains. ‘While there are potentially limitless modification patterns, we are learning some of the rules. We can predict from certain modifications as to whether that gene is active.’

Professor Mellor’s group works on yeast. ‘Yeast’s simplicity makes it a great system for understanding the basis of epigenetics,’ she says. ‘We’re able to look at the environmental signals that influence epigenetics and determine what it is that leads to chromosome modifications.’

For example, in everything from yeast to mammals, a starvation diet often allows you to live longer. Professor Mellor’s work has gained a handle on how this occurs. Under starvation conditions, or at least ‘calorific restriction’, she explains, ‘a different set of genes are brought into play to maintain metabolism and give enough energy to survive. This different set of active genes seems to allow yeast to live longer.’