08 December 2015

How to wake up silent genes?

Let them talk!

Leonid Andreev, "Search" No. 49-2015

"Everything in our life is much more complicated than it seems. And people working in science are convinced of this first of all, – one of the speakers of the scientific session, Corresponding Member of the Russian Academy of Sciences Vsevolod Kiselyov, began his story with such a philosophical introduction. Vsevolod Ivanovich, together with the Chief Scientific Secretary of the Russian Academy of Sciences, Academician Mikhail Paltsev, prepared a report on research in the field of regulation of gene activity and the creation of new drugs on this basis. It is quite possible that those who do not follow the latest developments in the field of genetics, after listening to this report, will adjust their views on this area of knowledge. 

– Until recently, we lived in the ideas of classical genetics, – says V.Kiselyov. – They mean that each of us inherits a genetic program from our mother and father. It has its own genetic encumbrances, mutations accumulate. As a result, there are offspring that carry the genome from two parents, and the whole life of the descendants is determined by the baggage of heredity that their genome acquired. We know that there are hereditary diseases, we have information about which of them are transmitted through the female or male line. And until recently, it was believed that there is always a violation of some gene behind this. A well–known example is the higher sensitivity of the northern peoples to alcohol due to its poor assimilation. In the inhabitants of the North, as a result of mutation, the gene responsible for the enzyme necessary for this works poorly. 

One of the most common hereditary diseases is associated with a mutation in the BRCA gene, a suppressor of tumor cell growth. This gene suppresses the development of cancer in the breast and ovaries. In mutant form, it is quite widespread, and about 5% of all cases of breast cancer are hereditary, or so–called family cancer, because the girl inherited a mutant gene from the female line. Normally, the BRCA protein suppresses the ability of cells to turn into cancer cells. If BRCA production is disrupted, then this protective function is lost and cells seeking tumor transformation can very easily become cancerous. 

By the way, in the USA all women are examined as part of a special screening program. If a mutation of the BRCA gene is found in a patient, she is offered to remove the mammary glands for the prevention of the disease. Angelina Jolie is a classic example, she has a hereditary BRCA mutation. Unfortunately, we do not have such a program. Although there is a lot of talk about its necessity.

But the most interesting thing is that when examining women with breast cancer, it turned out that in about 40% of cases, the BRCA gene is structurally perfect! However, he is silent at the same time! 

The recently implemented Human Genome program has demonstrated that everything in genetics is not as simple as it seemed before. Yes, of course, there are structural genes, and the concept of "one gene – one protein" as a basic one is fair. But at the same time, it turned out, for example, that the genome is oversaturated with different DNA sequences, seemingly meaningless, ballast. However, these DNA sequences play a huge role in regulating the expression of functionally important genes. It turned out that the genetic program according to which we live is predetermined not only by hereditary factors received from parents, but also by new genetic acquisitions. Starting from the stage of morphogenesis in the embryo and further throughout the life of the organism, the spectrum of gene expression is constantly changing.

Imagine an active gene that performs an important function. We thought that only an irreversible mutation could turn it off. It is known that the structure of the gene can be irreversibly disrupted under the influence of radiation, toxic chemicals, and because of this, it turns off from system operation. But it turned out that the gene can also "fall silent" as a result of the action of so-called epigenetic mechanisms, which differ from the processes occurring during mutation. Today, at least three mechanisms are known by which a gene, while maintaining its structure and remaining a combat unit, is functionally silenced. 

Of course, not all genes and not in all cells, but individual genes in some cells under the influence of a variety of conditions can undergo deep reprogramming. I will tell you about two key epigenetic mechanisms that are most interesting from the point of view of prospects for drug intervention in their regulation. 

Each cell is saturated with enzymes that regulate its daily activities. But certain factors can cause perturbation of enzymatic systems, causing them to damage the genome and the cell. Stimulators, or triggers, of this are external causes: smoking, prolonged stress, poor ecology, biological aging of the body. If such an effect lasts for a long time, then it affects the genome, and these changes are fixed.

Let's focus on two enzymes that play an important role in turning off genes: histone deacetylase and DNA methyltransferase. The first mechanism of harmful effects on genes is as follows. It is known that the gene is packed into a histone – a protein shell of a certain configuration that ensures its functioning. If histone deacetylase has processed this shell, then the configuration of the latter changes – it becomes denser. In this case, further transcription is blocked and the normal gene stops working. Although potentially it is still functional. 

The second mechanism is associated with another enzyme – DNA methyltransferase, which is also excited when exposed to various harmful factors and begins to introduce methyl groups into the gene, thereby modifying it and creating mechanical obstacles to its further work – the ability to form an RNA transcript. 

We call these processes epigenetic modifications, or "epimutations". 

Boris Vanyushin, corresponding member of the Russian Academy of Sciences, wrote for the first time about the methylation of the genome, that is, that mammalian DNA contains methyl groups. It was known that the DNA chain consists of four nucleotides: adenine, guanine, thymine and cytosine. Scientists wondered what the methyl groups that chemists found there 40 years ago were doing in the DNA molecule. And until recently, it remained unclear what the point was. And it turned out that this is a unique additional mechanism of gene regulation. 

It is very important that, unlike conventional genetic mutations, epigenetic modifications do not affect the structure of DNA and are potentially reversible. That is, they can be regulated by factors of the internal and external environment: nutritional characteristics, stress, drug therapy and even psychoemotional stimuli. 

It has been proved that epigenetic changes under certain conditions are able not only to persist during successive mitotic cell divisions, but also to be transmitted to three or four next generations. Although there were long disputes between supporters and opponents of epigenetics about this. The latter considered this approach to be a return to the ideas of Lamarckism with its "inheritance of acquired characteristics". 

So, both the first and second epigenetic mechanisms are reversible. And this means that if you act on cells with inhibitors of the enzymes histone deacetylase and DNA-methyltransferase, that is, to suppress their activity, then in the offspring of cells exposed to such an effect, the gene can restore its functions! 

Moreover, the offspring of these cells, after several divisions, can get rid of unhealthy baggage, because it was born in conditions when two excited enzymatic systems that reprogram the genome are in a suppressed state as a result of the action of an inhibitory drug. Thus, you return the original healthy genetic program to the cell. 

Once again, we emphasize that we see a fundamental difference between the epigenetic model and the so-called classical structural genetics, which believes that if a gene is damaged, then it is irreversible. There is only one way out – to change the gene to a healthy copy. By the way, today the approaches of gene therapy treatment are becoming a reality, and this area of knowledge is actively developing.

But with epigenetic changes, the situation is much simpler, since they affect the genome more plastically and are therefore reversible. And there is an opportunity – through medicines – to return a healthy program to the cell. 

About 10 years ago, in cooperation with MiraxbIopHarma, we started working with natural substances, in particular indole compounds and catechins of plant origin, with a very wide range of therapeutic effects. Over time, it became clear that these substances have the ability to suppress histone deacetylase and DNA methyltransferase. 

An article will be published in the next issue of the journal "Obstetrics and Gynecology", where we, together with the director of the Scientific Center of Obstetrics, Gynecology and Perinatology named after. Academician V.I.Kulakov academician Gennady Tikhonovich Sukhoi and professor from Kazan Larisa Ivanovna Maltseva write about the discovery of a very important fact that worries all women. Those of them who suffer from endometritis (inflammatory disease of the endometrium) complain of infertility. All attempts of such patients to get pregnant, even when they go to specialized clinics where they are planted with a fertilized egg, are in vain. 

The endometrium (the inner lining of the uterus) has a very important property – receptivity. That is, the endometrium must recognize and fix the fertilized egg in order for the embryo to begin growing. It turned out that this function in sick women is impaired. In this case, two genes are responsible for its formation – NOX10 and HOX11. When we took endometrial samples from patients suffering from infertility, it turned out that in almost all cases these genes were methylated, that is, they were functionally silent. 

I must say that two epigenetic drugs have already been registered in the USA, which inhibit the processes of gene methylation. Their effectiveness has been proven in some blood cancers. The third epi-drug is Indinol® Forto is registered in Russia and has already entered the pharmaceutical market. It is a drug that simultaneously suppresses DNA methyltransferase and affects histone deacetylase. The spectrum of its action is very wide, although the instructions contain recommendations only for the treatment of breast diseases. This was our conscious choice, as the increase in the incidence of breast cancer is becoming catastrophic. 

So, we decided to try whether it affects the cells of the endometrium. Indinol® Vorto was assigned to 25 women, and four of them successfully became pregnant after a course of taking it! 

Although from the point of view of evidence-based medicine, it is too early to draw final conclusions that the improvement was due to a specific impact, I repeat, indirect data confirm this. Moreover, we have observed the restoration of suppressor genes in pathologies such as endometrial hyperplasia and adenomyosis. There are in–depth clinical studies ahead, which, I hope, will help in the treatment of severe, socially significant diseases. 

If we return to the fundamental truths, we can confidently say that the classical genocentric concept has been radically revised today. The young scientific discipline of epigenetics, which allows for the possibility of reversing the flow of information from a function under the influence of various external and internal factors to a gene, will be one of the most studied and promising in biology. In terms of the significance of the discoveries made in this field and the scale of the prospects unfolding at the same time, both in fundamental science and in practical medicine, epigenetics is already ranked on a par with such epoch-making scientific achievements as Darwin's theory of evolution, Mendel's discoveries and the establishment of the structure of DNA. 

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