Unlike females, male mammals produce sex cells almost throughout their lives, starting at puberty. Spermogenesis impairment is one of the key factors in male infertility. Detailed study of its mechanisms has the potential to improve the lives of millions of people. In the United States, scientists have discovered a previously unknown property of a little-known enzyme that turns out to be essential for sperm production.
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A scientific paper describing the discovery and a series of experiments was published in the journal Genes and Development . It was written by scientists at University of Pennsylvania (USA) with participation from colleagues in China, Japan and other US institutions. The
DOT1L protein is present in many eukaryotic cells and in all mammalian cells . However, its role is poorly understood. The researchers analyzed the expression pattern of the gene encoding DOT1L and proposed that one of its key tasks is to regulate meiosis. This is a cell division in which the number of chromosomes is halved, and in animals, this is how germ cells are formed. To test this hypothesis, the scientists conducted a series of experiments in mice that disrupted the protein's role at different stages of the animals' development.
Since DOT1L apparently affects more than just the life cycle of germ cells, they did not focus on embryos - a reason for another study. Embryos with this enzyme "shedded" or "broken" simply do not survive. However, disruption of DOT1L function in the germ cells ( stem cells that produce gametes) of already born animals does not affect their ability to survive. The male mice seemed perfectly healthy, at least for a short time.
But regardless of the age of experimental exposure, spermatogenesis in this rodent quickly ceased. If the pups are "destroyed" by DOT1L in gonocytes (primary stem cells whose offspring become sperm), seed production begins after puberty but stops soon after. When the enzyme is blocked in adults, the clinical picture is similar except that it appears almost immediately.
The first round of germ cell division proceeds normally, but then the stem cells are quickly depleted. As a result, the mice consistently lost the ability to spermatogenesis due to the gradual degradation of the entire process.
The spermatogonia end first, then the first and second order spermatocytes, then the sperm cells, and finally the sperm itself. Theoretically, not only DOT1L that stops working could have this effect. So the scientists conducted controlled experiments.
Schematic representation of the spermatogenesis process with functional (left) and “available” DOT1L enzyme. The penultimate row of cells are spermatogonia (male germline stem cells), which after "turning off" or blocking the enzyme under study, rapidly "exhale" and are no longer able to divide.
Mouse germ cells were plated on nutrient media, but the enzyme itself was not blocked or removed. Instead, they obtained a drug that specifically interferes with the chemical activity of DOT1L in cells. The results were similar: the stem cell cultures actually did not grow. When these cells were transplanted into adult mice, they also quickly stopped spermatogenesis.
This discovery has the opportunity to serve in the treatment of infertility. The fact is that despite all the achievements of modern medicine, the factors that ensure the longevity of stem cells are still poorly understood. Especially if they are germ cells. In the future, the discovery of American scientists will not only allow the function of spermatogonia in mammals to be corrected, but also convert somatic cells (not sexual, but related to other parts of the body) into stem cells.
Another equally important aspect of the research The discovery is that the genomic region that regulates DOT1L is "responsible" for expression. This group of genes is called HoxC and, in turn, regulates the expression of a range of other genes.Furthermore, as the authors of the scientific work suggest, some of these genes are responsible for key properties of the stem cell life cycle. All these issues are raised for further research.
Over the past few decades, studies on the DOT1L (DOT1-like ) protein have shown that it plays an important role in chromatin formation. It is a complex of DNA and special proteins (mainly the histone ) that help package the huge molecule together with genetic information. At different stages of the life cycle, the degree of DNA compaction ( packing density ) changes by orders of magnitude. Furthermore, how tightly a part of the DNA molecule folds depends on its involvement in the transcription or replication process.
The basis of the DNA compact structure is the nucleosome . It consists of eight histone molecules (H2A, H2B, H3 and H4html type 1) around which the DNA is wound like a spool. Another type of histone (H1 in humans and other mammals, H5 in birds) keeps DNA out of "coiled" regions and confines nucleosomes. DOT1L participated in the formation of this formation.
It methylates the H3 histone in a certain part of the molecule, that is, it connects the methyl group -CH 3 to the amino acid (in this case, to the lysine ). As a result, the histone chemistry changes and plays a different role in nucleosome formation. What specific effects
DOT1L has on the functional processes of cells and organisms as a whole is not a fully understood question. This protein is known to play an important role in the pathogenesis of acute lymphoblastic leukemia and other diseases caused by mutations in the MLL1 (KMT2A) gene.
A study also published by Australian scientists in 2020 showed that DOT1L is crucial for the formation of humoral immunity . It is required for the formation of B lymphocytes in the bone marrow and determines their fate in the lymphatic system organs. Last April, an Italian research team proposed DOT1L as a promising target for anti-cancer treatment.
