New "-omika"
What is epitranscriptomics?
Maxim Rousseau, Polit.roo
Now scientists are increasingly talking about the existence of another mechanism regulating the work of genes – modifications of RNA molecules. A new term has already appeared for this field of research – epitranscriptomics. In the second half of June, an international conference on epitranscriptomics was held at the University of Chicago. The editors of the website of the journal Science briefly told about it.
The classic scheme of the work of genetic mechanisms consists of three links: DNA→RNA→proteins. Information is read from a gene located in the DNA chain, while a molecule of informational (or matrix) RNA is synthesized according to the principle of complementarity. Next, the matrix RNA enters the ribosome, where it serves as the scheme by which the protein corresponding to this gene is built. Synthesis of an RNA molecule based on a DNA sample is called transcription, protein synthesis based on an RNA sample is called translation. The genes recorded in DNA, in this case, turn out to be an unchangeable standard and can change only as a result of mutation: when a nucleotide is replaced in a DNA chain, a section of the chain is lost or inserted.
This scheme is certainly correct, but it does not take into account a number of other factors. And the genome of an organism does not actually work as a template for stamping unchangeable parts and not as a casting mold in which identical products are cast one after another. Rather, the genome can be compared to a literary scenario, according to which different directors will make similar, but still different films. Or with an orchestral score, which will sound differently under the guidance of different conductors. The fact is that in a living cell there are a number of mechanisms that affect the work of the genome. They can turn on a certain gene, activating its transcription, or turn it off, suppressing this transcription. The work of the cell on protein synthesis changes at the same time, although the sequence of nucleotides in DNA remains the same. All the ways in which genes are regulated without changing DNA are called epigenetic mechanisms.
There are several such mechanisms, and one of the most important among them is DNA methylation. The methyl group (CH3) attaches to cytosine, one of the nitrogenous bases in DNA. If there are many such methylated sites in a gene, then the DNA polymerase enzyme, which is busy reading information from the gene, will not be able to process it. Accordingly, the corresponding RNA chain will not be built (translation will not occur) and eventually the protein for which this gene is responsible will not be synthesized. Methylation of DNA sites thus serves as a method of switching off certain genes. For the proper functioning of many body systems, it is necessary that certain sections of chromosomes have the necessary "methylation profile", that is, that methyl groups are attached in the right places. There are even diseases associated with a violation of the methylation profiles of certain genes.
Later, scientists paid attention to the methylation of information RNA, not DNA. For the first time, RNA methylation was noticed back in the 1970s, but then they did not pay attention to it, since they mainly worked on studying DNA. Now, thanks to methods developed in the last decade under the leadership of Chuan He from the University of Chicago, Samie Jaffrey from Cornell University and Gideon Rechavi from Tel Aviv University, it has become possible to detect methyl groups in RNA molecules. It was found that a variety of RNA molecules are susceptible to methylation: transport, ribosomal, informational, small, long non-coding and microRNAs.
DNA methylation and RNA methylation differ in that, as already mentioned, cytosine is methylated in DNA, and in RNA, the methyl group in 80% of cases is attached not to cytosine, but to adenosine. But, as with DNA methylation, it prevents the reading of information and blocks the activity of the gene, only not at the transcription stage, but at the translation stage. Hence the name epitranscriptomics.
In 2012, Gideon Rehavi and his colleagues described one of the varieties of RNA methylation, which is designated m6A, where the digit indicates the position number in the adenosine molecule to which the methyl group is attached. This is carried out by a special enzyme m6A-methyltransferase. Now this type of RNA methylation is found in a variety of organisms: mammals, insects, plants, fungi, bacteria, even viruses have it. At the same time, in yeast and bacteria, m6A-methylated nucleotides were found with similar sites of ribosomal RNA.
In Chicago, Chuan He and his colleagues discovered that there is also a protein that produces the opposite effect, that is, removes m6A tags from the RNA molecule. It turned out to be the FTO protein encoded by a gene located on the sixteenth chromosome.
In 2016, a joint article by researchers from the USA and Israel was published in the journal Nature, devoted to another type of RNA methylation. This time, the methyl group is attached to adenosine at position number 1 (m1A). In general, scientists have come to the conclusion that the number of methylated nucleotides in RNA is about ten times greater than in DNA. Therefore, the role of RNA methylation may be very important.
Several modifications of the work of specific genes carried out by RNA methylation have now been studied. For example, it increases the expression of genes necessary for the proper differentiation of embryonic stem cells into cells of different types. Sometimes RNA methylation turns out to be harmful. There is a type of RNA methylation associated with an increased risk of diabetes. In myeloblastic leukemia, the addition of a methyl group to the RNA of blood cells prevents the transformation of blood stem cells (myeloblasts) into various types of leukocytes. In 2017, three groups of scientists independently showed that the removal of an enzyme that adds a methyl group to the informational RNA kills tumor cells in acute myeloblastic leukemia. Experimental drugs for the treatment of leukemia based on this effect are already being developed. At the current conference, Tony Kouzarides from the John Gurdon Institute in Cambridge told about another case of RNA modification associated with the occurrence of leukemia. He shared his suspicions that more such phenomena will be discovered.
In the new experiments of Chuan He's group, it was shown that m6A-methylation is critically important for brain development. Through proteins that read information from RNA, it is associated with the control of the exact time of formation of new neurons in the brain of mouse embryos, and also affects the restoration of axons after nerve damage. In one of the experiments, He and his collaborators found that m6A-methylation is also associated with memory mechanisms. When the gene that is responsible for the protein reading m6A tags from RNA was turned off, memory defects occurred in mice, but after they were injected with a virus carrying a functional variant of the gene, these defects disappeared. When the researchers chemically stimulated neurons to mimic the memorization of new information, they observed a sharp spike in protein synthesis associated with m6A.
It turns out that the modification of informational RNA is not limited to methylation. In a study by Shalini Oberdoerffer, it was found that in addition to methylation, there is RNA acetylation, in which the CH3CO-group attaches to cytosine. This modification stabilizes the information RNA molecule and, possibly, helps it to connect with transport RNA molecules.
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