A little-studied protein has been indispensable for the constant production of sperm

(ORDO NEWS) — Male mammals, unlike females, produce sex cells almost all their lives from the moment of puberty. Spermatogenesis disorders are one of the key factors in male infertility.

A detailed study of its mechanisms has the potential to improve the lives of millions of people. In the US, scientists have discovered a previously unknown property of a little-studied enzyme, thanks to which it turned out to be indispensable for the production of sperm

A scientific paper describing the discovery and a series of experiments that resulted in it was published in the journal Genes & Development . It was prepared by scientists from the University of Pennsylvania (USA) with the participation of colleagues from China, Japan, and other American institutions.

The DOT1L protein is found in many eukaryotic cells and in all mammalian cells. However, its role is poorly understood. The researchers analyzed the expression patterns of the genes encoding DOT1L and suggested that one of its key tasks is the regulation of meiosis.

This is cell division with a halving of the number of chromosomes, in animals this is how germ cells are formed. To test the hypothesis, the scientists conducted a series of experiments on mice, disrupting the work of this protein at different stages of animal development.

Since DOT1L obviously affects not only the life cycle of germ cells, they did not focus on embryos – this is a reason for another study.

Embryos with “off” or “broken” this enzyme simply do not survive. But disruption of DOT1L function in germline cells (stem cells that produce gametes) of already born animals does not affect their viability. At least in the short term, the male mice looked perfectly healthy.

But spermatogenesis in such rodents quickly ceased, regardless of the age of the experimental exposure. If the cubs were “broken” with DOT1L in gonocytes primary stem cells whose offspring become spermatozoa seed production began after puberty but then quickly ceased. When the enzyme was blocked in adults, the clinical picture was similar, only it came on almost immediately.

The first rounds of germline cell division proceeded normally, but then the stem cells quickly wore out. As a result, mice consistently lost the ability to spermatogenesis due to the gradual degradation of the entire process.

The spermatogonia ended first, the first and second order spermatocytes came next, followed by the spermatids, and finally the spermatozoa themselves. Theoretically, not only DOT1L that stopped working could be guilty of such an effect . Therefore, scientists conducted a control experiment.

A little studied protein has been indispensable for the constant production of sperm 2
Schematic representation of the process of spermatogenesis with a functioning (left) and with a “serviceable” DOT1L enzyme. The second row of cells from the bottom is spermatogonia (male germline stem cells), after “turning off” or blocking the enzyme under study, they quickly “exhale” and are no longer able to divide

Mouse germline cells were seeded on a nutrient medium, but the enzyme itself was not blocked or removed. Instead, they obtained a drug that specifically interfered with the chemical activity of DOT1L in cells. The result was similar: the stem cell culture practically did not grow. And when such cells were transplanted into adult mice, they also quickly stopped spermatogenesis.

The discovery has every chance to serve for the benefit of infertility therapy. The fact is that, despite all the achievements of modern medicine, humanity still knows very few factors that ensure the longevity of stem cells. Especially if they are germline cells.

In the future, the discovery of scientists from the United States will allow not only to correct the functions of spermatogonia in the body of mammals, but also to turn somatic (not sex, but related to the rest of the body) cells into stem cells.

Another equally important finding of the study was the localization of the genome region, for the regulation of the expression of which DOT1L is “responsible” . This group of genes is called HoxC and, in turn, regulates the expression of a whole range of other genes.

Moreover, as the authors of the scientific work suggest, a number of these genes are responsible for the key properties of the life cycle of stem cells. All these questions are proposed for further study.

Over the past couple of decades, research on the DOT1L ( DOT1-like ) protein has shown that it plays an important role in chromatin formation processes. It is a complex of DNA and special proteins (mainly histones) that help pack a giant molecule with hereditary information.

At different periods of the life cycle, the compaction (packing density) of DNA changes by orders of magnitude. Also, how tightly a section of a DNA molecule is folded depends on its participation in the processes of transcription or replication.

The basis of the compact structure of DNA is the nucleosome. It consists of eight molecules of histone proteins (types H2A, H2B , H3 and H4 ), around which, like a bobbin, deoxyribonucleic acid is wound.

Another type of histone ( H1 in humans and other mammals, H5 in birds) keeps the DNA outside of the “coiled” region and limits the nucleosome. DOT1L is involved in the formation of this formation .

It methylates the H3 histone in a certain part of the molecule, that is, it attaches a methyl group -CH 3 to the amino acid (in this case, to lysine) . As a result, the chemical properties of the histone protein change and it works differently during the formation of the nucleosome.

What specific effects DOT1L has on the processes of functioning of cells and whole organisms is not a fully understood question. This protein is known to play a significant role in the pathogenesis of acute lymphoblastic leukemia and other diseases caused by mutations in the MLL1 ( KMT2A ) gene.

Also published in 2020, a study by Australian scientists showed that DOT1L is critical for the formation of humoral immunity.

It is necessary for the formation of B – lymphocytes in the bone marrow and determines their fate in the organs of the lymphatic system. And last April, an Italian team of researchers proposed DOT1L as a promising target for anticancer therapy.


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