Epigenetics and diseases: a place to step forward

Epigenetics and disease: What it takes to get on the long road aheadTabitha M. Powledge (Genetic Literature Project), translated by Evgenia Ryabtseva

To date, the existence of a relationship between DNA and diseases is a generally recognized fact. However, this relationship remains vague. A huge number of components contribute to the development of pathologies such as cancer and Alzheimer's disease, but only relatively few of them are known for sure.

The researchers believe that the situation can be changed by the so-called Epigenome Atlas (Epigenome Roadmap) and about two dozen accompanying articles recently published in scientific journals. The atlas is a catalog of millions of epigenetic switches that control the activity of genes. It is quite obvious that epigenetics is the key to a real understanding of both diseases and the usual signs of the human body. Ultimately, this is true, but identifying and confirming these relationships will take a lot of time.

First of all, it turned out that disease-causing mutations and other DNA variations that affect various traits, ranging from growth to behavior, as a rule, do not even localize where we expect them to be: in genes encoding key proteins. 90% of disease–associated mutations are localized in DNA regions outside of these genes, or rather, in regulatory regions that control the activity of the protein-coding gene. According to the working hypothesis, the variability of predisposition to disease or any other trait mainly depends on minor differences in the expression of protein-coding genes whose activity is controlled epigenetically.

According to one of the unexpected and immediately practical findings published in the mentioned articles, the mutations associated with Alzheimer's disease are not active at all in brain cells, as one might expect. Instead, they alter epigenomic activity in immune system cells.

According to the head of this study, Li-Huei Tsai from the Massachusetts Institute of Technology, the results indicate that the suppression of neural mechanisms is not due to hereditary predisposition, even though it is one of the main signs of Alzheimer's disease. Instead, it can develop as a consequence of environmental factors and aging, as well as interaction with abnormally altered immune mechanisms.

The work was carried out on mice, so its results do not apply to humans. However, they have provided researchers with a promising new target for developing methods to prevent and treat this devastating disease, the problem of which in our aging society is getting worse every day.

Researchers who have devoted their work to the epigenome have also achieved some success in studying asthma and allergic diseases. They identified more than two dozen genes regulating the activity of immunoglobulin E (IgE) – antibodies that trigger and enhance allergic reactions. In some people, epigenetic mechanisms interfere with the inactivation of these genes at the right moment. The result is excessive production of IgE, which contributes to the development of an asthma attack. The head of this research project, Miriam Moffatt, claims that the identified genes are new potential therapeutic targets for the treatment of allergic diseases, as well as biomarkers that can be used to determine the response of patients to existing expensive treatments.

What is an epigenome?What exactly is an epigenome?

Thanks to the epigenome, all cells of the human body that are identical at the time of the beginning of division of a fertilized egg are able to acquire a narrow specialization and turn into cells of the brain, liver, heart, skin and other tissues. Due to the epigenome, identical twins with identical genomes always differ from each other (in some cases these differences are quite strong), these differences increase with age and quite often they develop different diseases. Thanks to the epigenome, we are very different from chimpanzees, despite the slight differences in our genomes.

The simplest explanation of the epigenome phenomenon is its representation as a system of biochemical switches that ensure the activation and inactivation of genes in certain cells at certain stages of life. Epigenetics try to explain how the environment – the food consumed, the attitude of parents, all the events that occur in life and, perhaps, even the events that occurred in the life of ancestors – forms an individual person. Due to these biochemical switches, external factors form the physiological characteristics of the body.

Explaining the relationship between the genome and the epigenome at a press conference dedicated to the publication of the above-mentioned series of articles (all of them published in the journal Nature and associated publications), one of the authors, Manolis Kellis from the Massachusetts Institute of Technology, said that all our cells have a copy of the same book [genome], however, they all read different sections, put notes on different pages and highlight different paragraphs and words.

The markings that Kellis was talking about are biochemical mechanisms that change the behavior of genetic material without changing the DNA sequence. The most well-known and most well-studied of these mechanisms are DNA methylation and histone modification.

Histones are proteins around which DNA strands are tightly wrapped. Histone modifications usually consist in the attachment of an acetyl group (CH ₃ CO). Acetylation helps a tightly twisted DNA molecule to loosen the tension slightly and facilitate access to genes for their activation or inactivation.

During methylation, methyl groups (–CH ₃) are attached to DNA, which, as a rule, suppresses gene expression.

Epigenetics in action: bright dots indicate methyl groups attached to DNA,
providing inactivation of genes.

It is this process that is described in the above-mentioned study devoted to the study of the mechanisms of asthma development. In the genomes of patients with asthma, the researchers found low methylation in 36 regions of 34 genes. As a result of the low level of methylation, these genes were not inactivated, which led to hyperproduction of the IgE initiating asthma attacks.

As part of the Health's Roadmap Epigenomics Program launched by the US National Institutes of Health (NIH), hundreds of researchers around the world studied epigenetic events in more than 100 types of tissues of healthy adults, as well as embryonic and stem cells, compiling a basic (reference) epigenome for each sample. These epigenetic profiles characteristic of each of the tissues can be compared with the profiles of other samples, including tissue samples of patients with various diseases, such as type 1 diabetes mellitus, Crohn's disease, hypertension, inflammatory bowel disease and Alzheimer's disease. This comparison allows specialists to identify epigenetic changes in certain types of cells.

Denial and warningsNot everyone thinks the epigenomic project is a grand idea.

Anonymous scientist, blogging on Homolog.us – Bioinformatics, complains that "over the past 4 years, nothing has been able to prevent the implementation of this expensive nonsense: neither the powerful criticism of the underlying scientific principles, nor the accusations of fraud brought against its leader, nor the public humiliation of the related ENCODE project, nor the reduction of NIH funding, nor protests by researchers, etc.".

As for the idea that exposure to toxins, parental behavior and other lifestyle factors determine the state of health, "none of the statements are confirmed by scientific data. We analyzed a lot of relevant papers and in many cases they were based on low-quality associative studies involving 30-40 people, conducted without further study of the causal mechanism."

This harsh condemnation reflects the opinion of a minority, and it is completely incorrect to talk about the weakness of all epigenetic research. However, the existence of such an opinion definitely indicates that, despite the noise raised around new publications, it is still very far from fully understanding the benefits of studying the epigenome for human health. The conducted studies should be reproduced again, and in the case of animal studies, reproduced with the participation of people. However, to date, the reproduction and confirmation of the results of epigenetic studies remains a difficult task.

Moreover, epigenetic activity changes throughout life, so there is a need to study its relationship with the aging process. In this regard, researchers have already planned to study the epigenomes of 1,000 additional cell types.

Kellis, who is the leader of the consortium working on the Atlas of the Epigenome and has been sharply criticized on Homolog.us , can definitely be called a fanatic of epigenomic research. However, even according to his consistently optimistic forecasts, it will take at least a decade to identify differences between the epigenomes of different people.

Portal "Eternal youth" http://vechnayamolodost.ru26.02.2015