Tuesday, November 24, 2015

Russian scientists have uncovered the essence of self-organization mechanisms in living cells – BBC

The chromosome – a structure that is inside the cell nucleus and carries a large part of the genetic information responsible for its storage, transfer and implementation. Chromosome formed from a very long DNA molecule is a double chain of a plurality of genes. If we consider that

core diameter does not exceed one-hundredth of a millimeter, while the length of a strand of DNA is about two meters, it is clear that the DNA must be packed very tight.

DNA “packed” and forms chromosomes during division only cells. But in between the divisions it is not just floating in the cell nucleus: in order not to get confused and do not tear molecule thin and long thread, as if the coil is wound on special proteins – histones and then rolled and arranged so that some sections of DNA strands are close to each other and interact. These “compact” regions are called topologically associated domains or Tadami. The area located between the Tadami (“Inter-tady”), in contrast, are characterized by a low level of interaction.

A group of Russian researchers, led by Sergei Razin (Head of the Department of Molecular Biology, Faculty of Biology, Moscow State University of Lomonosov , corresponding member of the Russian Academy of Sciences), studied how filamentous DNA-protein fibrils of chromatin stacked in three-dimensional structures – tady and inter-tady. The results of the scientists have been published in the journal Genome Research (the impact factor – 13.852), besides them in their review article informs magazine Nature Reviews Genetics .

Department of Science “Gazety.Ru” was able to talk with Sergei Razin, lead author published in Genome Research scientific article. The scientist told about the details of the work and that is why the results are extremely important for the world of genetics.

– Sergey, please tell us what is the role of chromosome located in topologically associated domains – tady? What are their differences from the regions located between them?

– At the core of any human cells having an average diameter of about 10 microns, done about 2 meters of DNA. It is clear that this DNA must be compactly stacked. The main problem is that, despite the high level of compaction of the genome as a whole, transcriptionally active regions should be available for various protein factors and enzymes that carry out transcription.

Earlier several authors have demonstrated that the genomes of Drosophila and mammals are organized into compact topologically associated domains – tady separated by some border areas.

The nature of these border areas remained unclear. Most authors believe that the very existence of these boundaries between compact domains due to the presence of special “dividing” genomic elements – insulators, mechanism of action that no one could explain. We have demonstrated that between Tadami arranged active regions of the genome containing genes that work in all types of cells (so-called genes “household”). Features chromatin working genes were sufficient to explain why such a chromatin simply can not be stowed in compact tady. The direct answer to your question is that the stores are tady unclaimed in a given cell type of genetic information – mainly tissue-specific genes work only in certain cell types. The activation of the transcription of these genes leads to dekompaktizatsii TADov – turning them into inter-tady.

– And what is the essence of your discoveries?

– From a conceptual point of view, the basic meaning of our work is that we have shown how the linear fibril chromatin itself fit a three-dimensional structure. This is a vivid demonstration of the mechanisms of self-organization in living cells. It is this component of the conceptual work has found an echo among colleagues around the world. Without exaggeration, we can say that here the entire Russian work has appeared at the peak of the world’s research.

The genomics of “breakthrough work” performed in Russia, it was not for many years.

This was possible also thanks to the interdisciplinary nature of the group of authors (biology, bioinformatics, physics, fundamentally important to confirm the conclusions of computer simulation has become possible due to the presence of MSU supercomputers “Lomonosov”).

– What is the sequel can get your job?

– Any good work serves as a platform for further research. Our work is no exception. Already, in the progress of a number of projects aimed at refining our model and obtaining new data on how interrelated structural and functional organization of the genome of a eukaryotic cell.

– What practical use could be made your conclusions – maybe in the future they could be used in medicine or in any genetic research?

– Louis Pasteur once said that there is no applied science. Yes (fundamental) science and its practical applications. New knowledge about how the genetic machinery of a living cell, sooner or later will be converted into practical solutions. In our case, there is good reason to believe that tady are both regulatory domain in which enhancers (small sections of DNA that increase the expression of genes. – “Times» ) can activate a variety of tissue-specific genes. Accordingly, the Association TADov a result of chromosomal rearrangements or separation can lead to a change in the spectrum of genes that are activated in some enhancer (superenhanserom).

This may be the cause of various diseases ( cancer, thalassemia, neurodegenerative diseases, etc.).

Knowledge of the mechanisms of certain diseases will allow to develop science-based strategies to treat them. In addition, at present, many pharmaceutical companies are actively developing the so-called “epigenetic drugs” that can, for example, cancer cells return to the path of normal differentiation (ie, force them to lose the ability to multiply uncontrollably). This work is currently being done largely at random (analyzed the effect of various compounds on the work of epigenetic mechanisms). In order to make searching for such drugs more meaningful, you must understand how epigenetic control of gene transcription. It is now clear that these systems affect the way the packaging of DNA into chromatin. Accordingly, the principles of disclosure of the three-dimensional organization of chromatin fibrils is a prerequisite for understanding the mechanisms of epigenetic systems, and so, and to develop strategies aimed interfere with the operation of these systems.

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