For many years the world of science has tried unsuccessfully to crack the riddle: how the human body manages to pack 2 meters of DNA into a tiny nucleus that is several thousandths of a millimeter in size.
The findings of the study published in the prestigious journal Molecular Cell show that building blocks (bases / nucleotides) of different types in the DNA chain are arranged gradually within the nucleus – from the periphery to the center, thus areas with a high concentration of building blocks of one type are in the periphery of The core, and as you progress to the center of the core the content of the building blocks gradually changes to other building blocks. Because the genes are located along the DNA, then the graded way in which the DNA is arranged within the nucleus separates the genes according to the content of their building blocks and so in effect the DNA is packaged within the tiny nucleus.
The important discovery was made by doctoral students Luna Tamar and Ofir Hameiri from the laboratory of Prof. Gil Est of the Department of Molecular Genetics of Humanity and Biochemistry at the Sackler Faculty of Medicine at Tel Aviv University. The study was conducted in collaboration with Prof. Bar Ilan, from Portugal, Spain, and the USA. The article was selected for the cover of the March 2022 issue of the prestigious journal Molecular Cell.
According to Prof Est, “Each of us has trillions of cells, and each cell has a nucleus in which our genetic code is packed, a sequence of DNA molecules we received from our parents – about 2 meters long. The DNA is complex From pairings of building blocks (bases / nucleotides) marked with the letters: G with C and A with T. In each region of the DNA there is a different division of these letter pairs.Our findings show that in the outer part of the nucleus DNA sequences are arranged. A. which are rich in nucleotide pairs A and T, and as they progress to the center of the nucleus there is a gradual shift so that the center of the nucleus is dominated by DNA sequences in which there is a wealth of pairs G and C. We have shown that this organization exists in almost all cells Of each gene in the nucleus affects the way the gene is expressed and consequently the processing of the messenger RNA (mRNA) generated from that gene. “Inside the nucleus so that genes whose products are processed by one mechanism will be in a different place in the nucleus of other genes with another mechanism. We believe this understanding will make a significant contribution to the development of genetic therapies for hereditary diseases and cancer.”
Gardens from the center and gardens from the periphery
Prof. Est explains that along the DNA are scattered activation zones – these are not the genes. The transcription of DNA into messenger RNA molecules that are translated into proteins that perform various functions in our body (for example, the vaccine injected into most of us against the corona virus consists of messenger RNA molecules of the virus that is translated in our body into the known spike protein. The vaccine to identify it and fight it in case of infection). The structure of a messenger RNA molecule is similar to a train, with each ‘caravan’, known as an axon, carrying within it a different genetic information, and cables of varying lengths being connected between the ‘carriages’. The messenger RNA is activated through a process known as splicing, in which the ‘carriages’ cling to each other, and then the cable connecting them is derived.
The study, which combined computational methods of bioinformatics with ‘wet’ biological experiments, identified a significant difference in the concentration of building blocks between genes located in the center of the nucleus and genes located in the periphery. It was also found that this difference also causes a difference in the nature of the mutations that lead to genetic diseases and cancer and in the way they affect the RNA messenger molecules: in mutations that are formed in genes in the periphery, the splicing process skips a ‘caravan’ Mutations in the genes in the center of the nucleus cause one of the cables connecting the ‘carriages’ not to be cut. In both cases, the messenger RNA translates into a completely disrupted protein that does not perform its function properly, and is therefore involved in the formation of a disease.
In addition, the researchers believe that the discovery may significantly advance innovative methods of genetic-molecular therapies for cancer and genetic diseases. The discovery may streamline and accelerate the development of drugs in a technology called “antisense therapy” (antisense therapy) designed to correct mutations by blocking disrupted regions in the genetic material in particular in the messenger RNA (mRNA). This method has already had important successes, For example, in the treatment of the genetic disease SMA, which causes muscle degeneration to the point of paralysis, today the development process for each disease individually is long and complex, and the new discovery may accelerate it significantly.
Put the “plaster” in the right position
Prof Est: “Our findings make an important contribution to understanding the way DNA is packaged in the cell nucleus, with areas rich in building blocks A and T located in the periphery, while those rich in C and G are in the center. We believe That the gradual separation between the two types of sequences within the nucleus is caused by phenomena of attraction and repulsion between electric charges within them, and in further research we will deal with this issue.
In addition, our discovery also contributes to the future development of innovative genetic therapies for cancer and genetic diseases. This is a method with enormous potential, which has already had encouraging successes – for example in the treatment of the genetic disease SMA, which causes muscle degeneration to the point of paralysis. As part of the method, a kind of ‘plaster’ is produced that penetrates the nucleus of the cell and is precisely positioned at the disrupted site in the RNA messenger, thus blocking the disrupted activity of the gene, and in fact correcting the mutation. To date, such drugs have been developed in a lengthy process of ‘trial and error’ until the right place is found in the RNA messenger to place the ‘band-aid’. Our findings direct drug developers to place each ‘plaster’ much more efficiently and accurately: in the center of the nucleus a blockage of ‘carriages’ is required, whereas in the periphery ‘plasters’ are needed that actually block the ‘cables’. We are now continuing to develop tools that will enable the rapid development of the right ‘plaster’ for each disease. “