Epigenetics show that the utilisation of the genome can be influenced

Keijo Viiri looks through the microscope at a “mini gut” grown from stem cells in the small intestine. The villi in the small intestine regenerate throughout life. In patients with the coeliac disease, the regeneration process is disturbed as a result of damage caused by gluten.

Keijo Viiri looks through the microscope at a “mini gut” grown from stem cells in the small intestine. The villi in the small intestine regenerate throughout life. In patients with the coeliac disease, the regeneration process is disturbed as a result of damage caused by gluten.

People receive their genes at conception, but the external environment plays a role in how the genes are expressed. Epigenetic mechanisms are involved in many diseases.

The fundamental rules of biology have had to be rewritten. The reason for this is new information on genes that has been obtained in recent years thanks to radically advanced research methods.

Postdoctoral researcher Keijo Viiri remembers the concept of Lamarckism from school biology classes: an organism can pass on traits that it has acquired during its lifetime to its offspring. People used to laugh at the idea – the necks of baby giraffes were not getting any longer even though the mother and father giraffes had to crane their necks in order to reach the leaves high up in the trees. It was not thought possible that acquired traits could be passed on to the next generation. Until…

“You cannot say that the giraffes’ necks are getting longer because they crane them so much. But at the micro level, something acquired seems to be involved in the genome. The genome constantly interacts with its environment and this phenomenon is what the new field of research, environmental epigenetics, is studying,” Viiri says.

Among others, Professor Michael K. Skinner from the Washington State University has written many scientific and popular articles on the topic.

For example, nutrition and environmental toxins edit the epigenetic level of the human genome. “Epi” means on top of something, and that is what the epigenetic level is: it is a plastic and functional layer on top of the genome – the hereditary material encoded in DNA – which is susceptible to environmental cues.

The best known and most studied case of epigenetic influence on a human population is the Dutch famine of 1944 caused by a German embargo at the end of World War II. For half a year, practically no food was supplied to an area in the west of Holland and as a consequence the population’s food intake dropped to about 500–600 kcal per day.

The children of women who were pregnant during the famine frequently had severe problems with their carbohydrate metabolism. In addition, the birth weight of children in the following generation was significantly higher. Even sixty years on, there are significantly higher rates of obesity and a greater incidence of diseases such as atherosclerosis and breast cancer in families who suffered in the famine. Research found that the methylation of the genes involved in growth and metabolism in the offspring had changed significantly. An environmental factor, i.e. the famine, had caused an epigenetic transformation.

Methylation: A chemical methyl group attaches to the DNA, affecting gene transcription. In addition, histone proteins packing the DNA may be methylated and this has an effect on gene transcription.

The epigenome changed especially in those children who were embryos when their mothers suffered from the severely restricted diet. The environment had a radical impact on the gene transcription and expression even decades later.

However, these children experienced the famine as embryos while being carried by the mother, so this is not yet a case of an actual epigenetic change inherited by one generation from another.

There are several epigenetic mechanisms, but we cannot talk about actual intergenerational epigenetic inheritance until an epigenetic transformation triggered by an environmental cue experienced by the pregnant mother is seen in her great grandchild. An environmental factor is always experienced by the foetus and its germline cells as well as by the mother. Thus, we can talk about epigenetic inheritance if the epigenetic modification is seen in the fourth generation.

“This is still quite unclear in humans, but research has shown that when nematodes were subjected to a certain smell, their offspring – even after 40 generations – were able to ‘remember’ the smell and react to it in a particular way,” Viiri says.
The effects of epigenetics on many cancers are currently being studied. For example, we now know that DNA methylation, one type of epigenetic modification, is involved in colon cancer.

Epigenetics can be perceived at two levels: as a wider phenomenon having an impact on the human genome or on the cellular level in the organs of the body.

The disease epigenetics research Viiri directs at the Tampere Center for Child Health Research does not investigate epigenetic heritability but the epigenetics involved in the function of the small intestine. The research focuses on coeliac disease, which is caused by the gluten in wheat, rye and barley.

When a person suffering from coeliac disease eats food containing gluten, the villi lining the intestinal wall is damaged. The villi are like long finger-like projections, but they shrink as the result of exposure to gluten. The function of the villi is based on the stem cells at their root. These stem cells, which proliferate throughout a person’s lifetime, constantly differentiate and become mature intestinal cells.

Differentiation: Stem cells possess the ability to transform into any tissue in the body.

 

Viiri’s research group first wanted to find out how epigenetics is involved in the differentiation of stem cells in the small intestine. The preliminary findings show that epigenetic regulation mechanisms are involved.

“We noticed that in coeliac patients, the differentiation of the stem cells in the small intestine is disturbed because of this regulation mechanism. Thus, the area able to absorb nutrients in the small intestine becomes considerably smaller.”

A frequently used metaphor is that in healthy individuals, the size of the absorbent surface of the small intestine is equal to the size of a tennis court, whereas in coeliacs this area shrinks to the size of just the court’s service box.
Viiri believes that the research results may later be used to improve the diagnosis of coeliac disease and to understand its pathogenesis.

“We’ve found epigenetically regulated target genes in the small intestine. Some of them have been screened and it looks like a certain epigenetic regulator is turned on too much as a consequence of an environmental factor, in this case gluten,” Viiri says.

When a person suffering from coeliac disease eats food containing gluten, the above mentioned mechanism maintains the disorder in the small intestine. In other words, gluten-triggered faulty epigenetic regulation at least partly prevents the normal function of the stem cells in the gut.

However, these findings will not necessarily help the treatment of the disease. According to Viiri, it might be dangerous to use drugs targeted at epigenetic regulators because the differentiation of several other tissues could also be inadvertently affected. Instead, the research findings may help the diagnosis of the disease and shed light on its pathogenesis.

Research on disease epigenetics at the University of Tampere is funded by the Academy of Finland, Tekes – the Finnish Funding Agency for Innovation, the Jusélius Foundation, the Päivikki and Sakari Sohlberg Foundation and the Finnish government.

 

In recent years, epigenetics has become a popular research topic in medicine. However, the underlying phenomenon is old and basic.

Researchers used to think that the human genome contained four different base nucleotides: adenine (A), thymine (T), cytosine (C) and guanine (G). However, it was more recently discovered that there are actually six nucleotides. The latest discoveries of so called methylated and hydroxymethylated cytosine, which environmental factors can effect, represent the epigenetic level.

The fact that the expression of certain genes depends on the parent the gene comes from was already discovered in the 1970s. If certain genes come to the child from the mother, they are repressed, i.e. those features are not evident in the child. But if the genes come from the father, they manifest themselves. Epigenetics can explain this phenomenon.

“The genome is like the hard drive of a computer and an epigenome is like the software on it. The epigenetic level, the soft level, decides which genes are switched on and off,” Viiri explains.

 

All cells contain the same genome with the exception of some white blood cells, but different cell types, for example in humans, are numerous. What is the system that guides the differentiation of cells? This problem has already interested Viiri in his studies.

“By the time I graduated with my doctorate, research methods had taken great leaps forward. It became possible to find out some things in one day that would have taken several years during my years of study.”

Viiri’s hypothesis was that epigenetics must also play a role in the differentiation of the stem cells in the small intestine. He worked as a postdoctoral researcher in the United Kingdom, but after receiving funding from the Academy of Finland, he returned to Finland to pursue this topic.

“Epigenetic research has been aided by high-throughput deep sequencing methods. Before they became available, sequencing was very slow.”

Sequencing: Mapping out the order of nucleotides in DNA.

 

It now only takes a couple of hours to sequence the whole human genome, and the cost is also no longer an issue. Such research methods are highly pertinent in epigenetic research.

Viiri is fascinated by the idea of the plasticity of the human genome in terms of its usage.

“Things are not so fatal, after all. It’s not like I got these genes and that’s it and nothing can be done about it. I find it great that these mechanisms can be studied.”

Viiri is not a clinical researcher; rather, he identifies as “a molecule geek”. He is interested in epigenetic phenomena in general, but it is of course important that the research can benefit actual patients.

“It is much more meaningful to investigate things when they have a clinical purpose. In many cases, the great discoveries are found in basic research and the findings can then be applied to nearly all diseases.”

 

In recent years, stories on epigenetics have also been published in Finland. Among others, one of Viiri’s fellow students published stories in the biggest national daily Helsingin Sanomat. She has studied the effect of alcohol consumption during pregnancy on the epigenome and foetal health.

Viiri says that epigenetics has raised the question of human responsibility – not only for one’s own health, but also for that of one’s descendants.

“One’s own behaviour may transform the epigenome and in doing so the health of one’s offspring. In some ways, it increases people’s personal responsibility. Here, we could add racy headlines from the Bible where it says that the iniquities of the father will be visited on the children and grandchildren to the third and fourth generations. But perhaps that is a bit too wild.”

Doctoral researcher Mikko Oittinen (left) works on Keijo Viiri’s project on disease epigenetics. The research is part of a wider consortium working on coeliac disease at the University of Tampere.

Doctoral researcher Mikko Oittinen (left) works on Keijo Viiri’s project on disease epigenetics. The research is part of a wider consortium working on coeliac disease at the University of Tampere.

Text: Tiina Lankinen
Photographs: Jonne Renvall