The mechanism of DNA self-packaging
MSU scientists investigated the mechanisms of self-organization in a living cell
MSU Press Service
A chromosome is a structure that is located inside the cell nucleus and carries most of the genetic information, responsible for its storage, transmission and implementation. A chromosome is formed from one very long DNA molecule, which is a double chain of many genes. If we consider that the diameter of the nucleus does not exceed one hundredth of a millimeter, and the length of the DNA strand is about two meters, it becomes clear that the DNA must be packed very tightly.
DNA is "packed" and forms chromosomes only during cell division. But in the interval between divisions, it does not just float in the nucleus of the cell: in order not to get tangled and not to break, the molecule is wound with a thin and long thread, as if on a spool, on special proteins – histones, and then folded and arranged so that some parts of the DNA strand are close to each other and interact. Such "dense" regions are called topologically associated domains, or TADs. The areas located between the TADs ("inter-TADs"), on the contrary, are characterized by a low level of interactions.
A group of Russian researchers led by Sergey Razin (Head of the Department of Molecular Biology, Faculty of Biology, Lomonosov Moscow State University, Corresponding Member of the Russian Academy of Sciences) studied how filamentous DNA-protein chromatin fibrils fit into three-dimensional structures – TADs and inter-TADs. The results of the scientists' work were published in the journal Genome Research (impact factor - 13,852) – Ulianov et al., Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains; in addition, they are reported in their review article by the journal Nature Reviews Genetics (Moving a TAD closer to unravelling chromosome architecture).
"Coils" "push" – genes change"Previously, a number of authors demonstrated that the genomes of mammals and drosophila are organized into compact topologically-associated domains – TADs separated by some border areas, – says the head of the work Sergey Razin.
– The nature of these border areas remained unclear. Most authors believed that the very existence of these boundaries between compact domains is due to the presence of special "separating" genomic elements – insulators, the mechanism of action of which no one could explain. We have demonstrated that between the TADs there are active regions of the genome containing genes that work in all types of cells (the so-called "household" genes). The chromatin features of the working genes turned out to be sufficient to explain why such chromatin simply cannot be stacked in compact TADs."
Russian scientists have managed to show how the DNA-protein fibrillation itself fits into a three-dimensional structure. This is a vivid demonstration of the work of self-organization mechanisms in a living cell. It is this conceptual component of the work that has found a response among researchers all over the world.
Genes turn on and off – diseases arise"It is no exaggeration to say that here the entire Russian work was at the peak of world research.
In genomics, there have not been such “breakthrough works” performed in Russia for many years. This was made possible, among other things, thanks to the interdisciplinary nature of the team of authors (biologists, bioinformatics, physicists; computer modeling, which is fundamentally important for confirming the conclusions of the work, was made possible thanks to the presence of the Lomonosov supercomputer at Moscow State University)," says Sergey Razin.
The conclusions made by Russian researchers can serve as a basis for important practical developments: scientists have good reasons to believe that TADs are simultaneously regulatory domains within which enhancers (small DNA regions that enhance gene expression) can activate various tissue-specific genes. Accordingly, the combination of TADs as a result of chromosomal rearrangements or their separation can lead to a change in the spectrum of genes activated by one or another enhancer, and this can be the cause of various diseases.
A new approach to old diseasesAccording to Sergey Razin, knowledge of the mechanisms of formation of these diseases will allow developing scientifically sound strategies for their treatment: currently, many pharmaceutical companies are already actively developing so-called "epigenetic drugs" that can, for example, make cancer cells lose their ability to multiply uncontrollably.
However, this work is currently largely done at random, by analyzing the effect that various compounds have on the work of epigenetic mechanisms. In order to make the search for such drugs more meaningful, it is necessary to understand how epigenetic gene transcription control systems work. It is now clear that these systems affect the way DNA is packaged in chromatin. Accordingly, the disclosure of the principles of the three-dimensional organization of chromatin fibrils is a prerequisite for understanding the mechanisms of epigenetic systems, and, therefore, for developing strategies to influence the work of these systems.
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25.11.2015