How does the human body pack 2 meters of DNA into a tiny nucleus that is only a few thousandths of a millimeter in size

Since the genes are found along the length of the DNA, then the staggered way in which the DNA is arranged inside the nucleus separates the genes according to the content of their building blocks and thus the DNA is actually packed inside the tiny nucleus

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 inside a tiny nucleus that is only a few thousandths of a millimeter in size. Now a path of researchers from Tel Aviv University may advance science in a significant way towards solving the mystery.

From the findings of the study published in the journal Molecular Cell, it appears that building blocks (bases/nucleotides) of different types in the DNA chain are arranged in a graded manner inside 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 nucleus and so on As you progress to the nuclear center, the content of the building blocks gradually changes to other building blocks. Since the genes are found along the length of the DNA, then the staggered way in which the DNA is arranged inside the nucleus separates the genes according to the content of their building blocks and thus the DNA is actually packed inside the tiny nucleus.

The important discovery was made by doctoral students Luna Tamar and Ofir Meiri from the laboratory of Prof. Gil Est from the Department of Human Molecular Genetics and Biochemistry at the Sackler Faculty of Medicine at Tel Aviv University. The research was conducted in collaboration with Prof. Rodad Sharan from the School of Computer Science at Tel Aviv University as well as researchers from Bar Ilan University, from Portugal, Spain, and the USA. The article was selected for the cover of the March 2022 issue of the prestigious journal Molecular Cell.

The spatial arrangement affects gene expression

Prof. Ast: "There are trillions of cells in the body of each of us, and each cell has a nucleus inside which our genetic code is packed, a sequence of DNA molecules that we received from our parents - which is about 2 meters long. The DNA consists of pairs of building blocks (bases/nucleotides) marked with letters: G with C and A with T. Each region of the DNA has a different distribution of these letter pairs. Our findings show that in the outer part of the nucleus there are DNA sequences that are rich in A and T nucleotide pairs and as you move towards the center of the nucleus there is a gradual replacement so that in the center of the nucleus DNA sequences dominate where there is a wealth of G and C pairs. We have shown that this organization exists in almost all cells in our body. We also showed that the position of each gene in the nucleus affects the way the gene is expressed and, as a result, the processing of the messenger RNA (mRNA) generated from that gene. Understanding how the genetic material is arranged in the nucleus allows us to estimate that the sequence of DNA molecules is organized within the nucleus so that genes whose products are processed by one mechanism will be in a different place in the nucleus than other genes with a different mechanism. We believe that this understanding will make a significant contribution to the development of genetic therapies for hereditary diseases and cancer."

Prof. Ast explains that along the length of the DNA are scattered activation regions - the so-called genes. The transcription of the DNA into messenger RNA molecules that are translated into proteins that perform various actions in our body (for example, the vaccine injected to most of us against the corona virus consists of messenger RNA molecules of the virus that are translated in our bodies into the known spike protein, this caused the system the vaccine to identify it and fight it in case of infection). The structure of a messenger RNA molecule is similar to a train, where each 'car', known as an axon, carries different genetic information, and between the 'cars' cables of varying length are connected. The messenger RNA is activated through a process known as splicing, where the 'cars' stick together, and then the cable connecting them is derived.

The discovery opens the door to innovative methods of molecular genetic therapies

As part of the study, which combined computational methods of bioinformatics with 'wet' biological experiments, a significant difference was identified, in the concentration of the 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 messenger RNA molecules: in mutations that are created in peripheral genes, the splicing process skips a 'car', and connects the one before it to the one after it, and in contrast Mutations in the genes in the center of the nucleus mean that one of the cables connecting the 'cars' is not derived. In both cases, the messenger RNA is translated into a completely defective protein that does not perform its function properly, and is therefore involved in the creation of a disease.

In addition, the researchers believe that the discovery may significantly promote innovative methods of genetic-molecular treatments for cancer and genetic diseases. The discovery may streamline and accelerate the development of drugs using a technology called "therapy with the help of an antisense molecule" , for example in the treatment of the genetic disease SMA which causes muscle atrophy to the point of paralysis. Today the development process for each individual disease is long and complex, and the new discovery may speed it up significantly.

Prof. Ast: "Our findings make an important contribution to understanding how the DNA is packaged in the cell nucleus, where areas rich in building blocks A and T are located on 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 inside the nucleus is caused by the phenomena of attraction and repulsion between electric charges within them, and in further studies we will deal with this issue.

In addition, our discovery also contributes to the future development of innovative genetic treatments 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 atrophy to the point of paralysis. As part of the method, a kind of 'band-aid' is produced that penetrates the cell nucleus and is positioned precisely at the disrupted site in the messenger RNA, thus blocking the disrupted activity of the gene, and in fact correcting the mutation. To date, drugs of this type have been developed in a lengthy process of 'trial and error' until the right place in the messenger RNA to place the 'band-aid' is found. Our findings direct the drug developers to place each 'band-aid' in a much more efficient and precise manner: in the center of the nucleus, blocking of "cars" is required, while in the periphery, 'band-aids' are needed that block the "cables". We are now continuing to develop tools that will enable the rapid development of the correct 'band-aid' for each disease."

for the scientific article

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