Fantom 5: from reading the genome to decoding it
A man and a mouse can hardly read DNA
Scientists have explained why all cells are different and why a person does not look like a mouseNadezhda Markina, <url>
The Russian participant of the Fantom project, bioinformatician Vsevolod Makeev, told the newspaper.Ru" about the tasks of the work and how it was conducted.
The main mystery of lifeReading the sequence of letters in the human genome does not yet give an understanding of how the genome works.
This is not a genome decoding, but, on the contrary, an encrypted text, the meaning of which we do not yet understand. The main intrigue lies in the fact that all cells of the body have the same DNA, which contains information about the coding of certain proteins. But the cells of different tissues are different, muscle cells are not like nerve cells or blood cells. In the process of development, each organism goes from a fertilized egg to an adult and at the same time changes all the time, but the genome does not. It is obvious that the work of genes is not the same in different places and at different times. How it's all regulated is the main mystery of life.
In the last decade, the efforts of scientists have been aimed at consistently getting closer to understanding how the genome works. A big step in this direction is described in two articles in the latest issue of the journal Nature, where the results of research under the Fantom program (An atlas of active enhancers across human cell types and tissues and A promoter-level mammalian expression atlas) are published.
The name of this program stands for Functional ANnoTation Of Mammals – a functional characteristic of the mammalian genome. It was initiated in 2000 by Japanese scientists from the RIKEN Life Sciences Technology Center. The implementation of the program includes several stages, and now scientists are publishing the results of the fifth stage. More than 250 scientists from 114 institutes from 20 countries, including Russian specialists from the Institute of General Genetics of the Russian Academy of Sciences, participate in the international consortium. In addition to two key articles in Nature, the results of research on the Fantom 5 project have also been published in 16 articles in other scientific journals.
The principles of the genome are universal for both mice and humans – these representatives of mammals have become the main objects of research. Humans and mice have about the same set of genes, at the same time we are not at all like a mouse. The thing is that human genes are regulated differently than mouse genes. Scientists were convinced of this by mapping these regulators and comparing how they work in one and another species.
"The research gives us a glimpse into why humans are different from other animals, despite the fact that we share most of the genes with them," says Martin Taylor from the Institute of Genetic and Molecular Medicine at the University of Edinburgh. "A comparison of the human and mouse atlas shows that there has been a significant rewiring of the connections between regulators in the process of evolution."
A person is also different in different tissues. The secret of the fact that liver cells are not like blood cells, again, is that different genes work in them. And which genes work, which ones don't, depends on regulation.
Gene RegulatorsThe main regulators of the genome are the so–called promoters and enhancers.
A promoter is a sequence of nucleotides that gives rise to transcription – the first stage of the gene's work, when matrix RNA is synthesized on a DNA site according to the principle of complementarity. The signal to this occurs when the promoter is recognized by the enzyme RNA polymerase. An enhancer is a multiplier of the work of a gene, a sequence of nucleotides that may not be located near the gene at all, but somewhere quite far away. But, acting through certain proteins, the enhancer can increase the transcription of a particular gene several times.
Determining the location of these promoter regulators and enhancers in the genome is a very difficult task that can only be solved by the efforts of a large consortium. This task was solved in the Fantom program. For example, scientists from the Roslin Institute at the University of Edinburgh have created an atlas of regulators of gene activity in the development of muscles and bones.
The researchers used a special technique called Cap Analysis of Gene Expression (CAGE), created at the RIKEN Center. It made it possible to track the activity of promoters and enhancers in more than 180 types of human cells.
Scientists were able to identify 180 thousand promoters and 44 thousand enhancers in the genome. They found that transcription regulation is very much specific to each cell type.
Russian scientists at FantomThe consortium of the Fantom 5 project includes a team of Russian bioinformatics from the Institute of General Genetics of the Russian Academy of Sciences.
About this work "Newspaper.En" said Vsevolod Makeev, Doctor of Physical and Mathematical Sciences, Head of the IOGen RAS Department, coordinator of the Russian group.
– How long have you been involved in the project?
– We joined the Fantom consortium in 2011, at the Fantom 5 stage. When it became possible to obtain data for a large number of tissues, the project managers attracted bioinformatics from all over the world. By gaining access to unique data before they are published, bioinformatics, in turn, offered data processing methods and ideas that can be verified by these methods.
– How is your work organized?
– All data is stored on servers, we download and analyze them, and this can be done while in Moscow. We use powerful computers for this at the Faculty of Bioengineering and Bioinformatics of Moscow State University and at home in IOGEN.
– And what specific tasks did you face?
– We studied the activity of regulatory regions of the genome and proteins – transcription factors that interact with these proteins. Five groups worked on this, and this is the majority of all research groups in the world that solve these problems. As a result, it was possible to compile an atlas of the activity of regulatory proteins in different cells – this is about 1,500 proteins. But the regions in which they interact with DNA are known so far for less than half of the regulators. It was also possible to identify the role of a chemical change in DNA, the so-called methylation, in the binding of regulatory proteins to DNA.
– How was the development of research from the first to the fifth Fantom? And at what facilities did the scientists work?
– Since 2000, the technology has changed at least three times, and new methods have made it possible to conduct more and more extensive and accurate research. And as for the objects, it was originally a mouse, and the letter "M" in the abbreviation meant Mouse. Now it's a mouse and a man
– What is the difference between the Fantom project and the Encode project, the results of which were published not so long ago?
– Mainly because we analyzed not cancer lines, but normal cells. Cancer lines are easier to work with, but they do not always reflect well the processes in normal cells. Such a broad analysis of normal tissue cells has never been carried out before. Thanks to this, it became possible to understand why tissue cells have such a cellular type as they have. This is also important for regenerative cell medicine – to understand how the differentiation of cells in tissues works. And in general, this is a fundamental question of biology.
– Is there already an understanding of why cells become different and how the genome works?
– Now we more or less understand which genes work in which cells, and these are not necessarily genes that encode proteins. But the more interesting question is why, for example, 10 thousand genes are included in some tissue, and the rest do not work. Why gene promoters turn on and off. We do not yet understand this so well that we can control this process, so that we can, say, design regulatory elements, insert genetically engineered sequences into the genome and say that this gene will work in such and such tissues, but it will not work in such and such tissues.
– Will there be a continuation of the project?
– Yes, the results of the first stage of Fantom 5 have been published now, and the results of the second stage will probably be published in 2015. The possibilities of further continuation of the project are also being discussed.
It remains to understand how the plane flies"We are multicellular organisms consisting of at least 400 cell types.
This remarkable diversity of cell types allows us to see, think, hear, move and resist infections, while all this information is encoded in the genome, the same in all cells. The differences between cells are exactly which part of the genome they use. For example, brain cells use genes that are not used in liver cells, and therefore the brain and liver work differently. Within the framework of the Fantom 5 project, we have for the first time found out exactly which genes are used in each of the cells of the human body and which parts of the genome control this," said Dr. Alistair Forrest, an employee of the RIKEN center, scientific coordinator of the Fantom 5 project.
The peculiarity of the project is that it is aimed at studying normal, healthy cells, the so-called primary, not genetically altered, not cancerous. To understand how the genome works, you need to do it in healthy cells. But in the future, the same methods will allow us to study the gene activity in pathological cells in patients with a variety of diseases in order to understand the mechanism of breakdown at the molecular level.
Professor David Hume, director of the Roslin Institute at the University of Edinburgh, using the analogy of an airplane, said: "We have made a leap in understanding how individual parts of an airplane work. And we learned quite a lot about how they interact with each other to eventually understand how the plane flies."
Portal "Eternal youth" http://vechnayamolodost.ru28.03.2014