SDA for genes

"Traffic lights" in DNA help to control the activity of genes

Kirill Stasevich, Science and Life (nkj.ru ), according to the materials of the MIPT press service.

Any living cell must constantly respond to changing conditions around itself and in itself. And this means that she needs to constantly turn on some genes, then turn off others, then slightly lower the activity of others, etc. On the other hand, in the body of a single person there are a great many very different cells – muscle, nerve, etc. – which have the same set of genes: after all, they belong to to the same individual. It is quite clear that different genes work in different cells at the same time, and some are silent almost all their lives, while others work almost all their lives. In other words, living organisms must have very effective and diverse tools to manage their DNA.

The information stored in genes is activated in several different stages: first, a copy of it is synthesized on a gene – that is, on a DNA fragment – in the form of an RNA molecule; then various molecular modifications occur with this RNA; then it is picked up by protein synthesizing machines and a polypeptide chain is assembled on it - in accordance with the instructions written in RNA. 

There are regulatory mechanisms at each stage. For example, the synthesis of an RNA copy on a gene (this is called transcription) begins when special proteins - transcription factors – bind to DNA. They themselves can be active and inactive. If the cell receives some signal from the outside, then the receptor protein that received the signal will transmit it through a number of intermediary molecules to a certain transcription factor, which is activated and will start transcription (that is, RNA synthesis) on a certain gene.

Another mechanism, also related to the transcription stage, is called epigenetic regulation. More precisely, there are several mechanisms under this name, and we have repeatedly recalled them: epigenetic regulation includes manipulations with histones – DNA packaging proteins, and the work of special RNA molecules, and modifications of DNA itself by methyl groups.

DNA methylation by the nitrogenous base cytosine – the genetic letter C. (Illustrations: @tsarcyanide, MIPT press service).

Epigenetic mechanisms allow or prohibit transcription – that is, they allow or prohibit proteins that synthesize RNA copies to work with DNA. The DNA itself does not change at the same time, which is why such mechanisms are called epigenetic – that is, acting on top of the genetic text. Epigenetic control methods can last for a very long time, almost a lifetime; an epigenetic program can even be passed on to other generations. It's just that the regulatory "switch", which turned out to be in the "on" or "off" position, remains in this position for a very long time.

Moreover, there are many subtleties in the work of epigenetic methods of gene regulation. For example, if we are talking about methylation and demethylation of DNA, do not think that methylation, for example, is always the "euthanasia" of a gene, and demethylation is activation; it all depends on where the methylation/demethylation happened. DNA is a double chain of nucleotides – nitrogenous bases connected to sugar and phosphoric acid; four types of nitrogenous bases, A, T, G, C are the same four genetic letters encoding everything that is needed for life. Methyl groups (CH3) are most often attached to the letter C – cytosine, and to cytosine, next to which is G – guanine (dinkuleotide CpG, where p is the residue of phosphoric acid).

The isolated part is a CpG dinucleotide, on the right is a double DNA chain.

The methyl group can attach to cytosines standing in different places of DNA, and it will act in them in different ways. For example, if methyl groups sit on DNA around the site from which transcription begins (that is, the synthesis of an RNA copy), then in this case the gene will most often be silent. If the methyl groups are inside the gene, far from the start point of transcription, then the gene is usually active.

But both at the beginning of transcription and inside the gene there are many cytosine-guanine pairs that can be promethylated. Are these pairs the same? Researchers from the Institute of Biotechnology of the Russian Academy of Sciences have previously shown that if you compare the activity of a gene with methyl modifications of certain cytosines, then some of the CpG pairs are particularly closely related to the state of the gene. Such pairs were called "CpG traffic lights". 

In an article published in the journal BMC Genomics (Lioznova et al., CpG traffic lights are markers of regulatory regions in human genome), employees of the FITZ Biotechnology RAS and their colleagues from the King Abdullah University of Science and Technology (Saudi Arabia), the Moscow Institute of Physics and Technology (MIPT), the Institute of Mathematical Problems of Biology The Russian Academy of Sciences and a number of other scientific centers write that the methyl groups on the "traffic lights" better show the activity of genes than if we look at the methylation of the entire DNA section, whether in the zone of the beginning of transcription or throughout the gene.

In addition, the authors of the work noticed that there are especially many epigenetic "traffic lights" in DNA sites called enhancers. Enhancer sequences activate genes, but they can be quite far away from their genes (we have already written once about how they manage their wards with their remoteness). Enhancers are a necessary tool for regulating genetic activity, and methyl groups help fine–tune regulation: the methyls on the "traffic lights" in enhancers affect how proteins responsible for gene transcription will interact with them. According to the authors of the work, "CpG traffic lights" rarely mutate - obviously, damage to the traffic light due to its special significance is quickly washed out by natural selection: an individual with such a mutation does not have time to leave offspring.

Epigenetic regulation in general and DNA methylation in particular are associated with a variety of biological processes, and violations in "epigenetics" often lead to severe pathologies. Abnormal DNA methylation can be found in cancer, metabolic disorders, cardiovascular, neurodegenerative and other diseases; and many research groups are now actively looking for drugs that would act precisely at the epigenetic level. So everything we can learn about this is extremely important both from a fundamental and practical point of view.

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