Three-dimensional genome
New evidence of the significance of the 3D structure of the genome has been found
and the possibility of transferring it by inheritance
Alina Chernova, "Biomolecule"
Science is finding more and more evidence that not only genes, but also many other factors are responsible for the way we are born.
Apparently, in addition to the genetic code and a variety of regulatory molecules, it also matters how genes are stacked in the nuclei of our cells.
(In the picture from the website roboticstomorrow.com a three-dimensional model of the human genome is shown).
DNA molecules are very large, and packing them into a small nucleus is an art. A recent work by Russian researchers highlights the nuances of such packaging in the somatic and germ cells, emphasizing the conservativeness of this feature of the genome.
A group of scientists from Novosibirsk and Moscow conducted a study comparing the spatial organization of the sperm genome with the genome of fibroblasts (connective tissue cells that are often used in various experiments), and published an article in the journal Genome Biology [1]. The work studied spermatozoa – cells with the densest DNA packaging (due to their small size) – and showed that the features of DNA packaging do not affect the large-scale organization of the genome. The 3D structure of the sperm genome, despite the differences, turned out to be similar to the structure of the genome of fibroblasts, as well as other cells studied earlier.
The Hi-C method was used in the work [2, 3], which is used to detect interactions between different parts of the genome. First, all sections of the genome are stitched together in space, which is achieved by processing DNA with formaldehyde. After that, the entire genome is cut into small pieces with special restriction proteins and dissolved in a relatively large volume of water, which allows the fragments to be separated at a great distance from each other due to dilution. Then all the sections are stitched in random order, and it remains only to determine which DNA fragments are stitched together, that is, which of them were close to each other. To do this, sequencing is used – a method for determining the sequence of nucleotides in DNA. Based on the results of this experiment, contact matrices are constructed that demonstrate the frequency of interaction of different parts of the genome with each other, which gives an idea of the 3D organization of DNA in the nucleus.
The graphical representation of the contact matrix is a table, in the rows and columns of which all sections of the genome are sequentially laid down, starting with the first chromosome and up to the last (the numbers are indicated next to the matrices), and in the cells of the table the relative frequency of contacts between the two corresponding loci is indicated in color. The red color means the largest number of contacts, and the blue color means the minimum. It can be seen from the results of the experiment that similar patterns are observed in spermatozoa and fibroblasts. Despite the denser packing of the sperm genome and the inactivity of their genes, the 3D organization of DNA in two types of cells is similar (Fig. 1).
Figure 1. Matrices of spatial DNA contacts of fibroblasts and spermatozoa. Full-genome matrices of spatial contacts of DNA of spermatozoa (a) and fibroblasts (c) and intra-chromosomal contacts of chromosome 19 (b, d) for these cell types are shown. Red color means the largest number of contacts, and blue color means the minimum number of contacts. The white stripes correspond to non-mapped areas. Figure from [1].
The data obtained are important for understanding how the genome works, how individual genes coordinate their activity. There are examples when seemingly insignificant mutations lead to serious changes in the spatial organization of DNA, which in turn leads to catastrophic consequences for the body. Understanding how the genome works opens up new opportunities for the prevention and treatment of diseases.
"The spatial organization of the genome is now one of the hot topics in biology, as it became clear that the way DNA is laid in the nucleus, which sections of a long DNA molecule are brought together in space, and which are spaced apart from each other – all this greatly affects the activity of genes. Thus, the 3D organization of the genome is still a little-studied, new level of regulation of the work of genes. Spermatozoa are a real godsend for understanding the principles of this level of regulation. The fact is that their DNA is packed into the nucleus in a fundamentally different way than in all other cells of the body. All the genes of a mature sperm are inactive, which means that it is possible to understand how the work of genes affects the organization of the genome. Spermatozoa carry only half of the normal set of chromosomes, and this feature allows you to more accurately analyze the contacts of different chromosomes in the nucleus. If we talk about the results, they were quite unexpected for me – all these features practically have no effect on the large-scale 3D organization of the genome. That is, on a large scale, the sperm genome is laid out in the same way as in the other previously studied cells. This is an interesting result also because spermatozoa transmit their genome to the next generation, and now we know that in addition to genetic information (a set of DNA), the 3D structure of DNA molecules is also transmitted," Nariman Battulin, the first author of the publication in Genome Biology, says.
Researchers will continue to work on this issue. It is planned to study the specific 3D organization of the sperm genome at more subtle levels. Also, following the classical principle in biology, "If you want to know how it works, break a part of it and see what happens," scientists have started a project to experimentally change the spatial organization of the genome in mouse embryonic stem cells.
Literature
- Battulin et al. (2015). Comparison of the three-dimensional organization of sperm and fibroblast genomes using the Hi-C approach. Genome Biol. 16, 77;
- Biomolecule: "The mysterious journey of non-coding Xist RNA on the X chromosome";
- biomolecule: "Stories from the life of the X-chromosome of the hermaphrodite roundworm".
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03.03.2015