How does the mechanism that silences genes that are not necessary for cell activity work
All the cells in the body have the same genetic load, and one of the biggest puzzles in biology is how cells in the various tissues "know" to activate only the genes necessary for the function of the tissue in which they are located. The decision which genes will be expressed in each tissue falls already at the beginning of embryonic development. At this stage two types of genes can be distinguished in each cell. The first type are genes that are activated in all the cells of the body and produce proteins that play maintenance roles in the cell - control of metabolism, creation of energy from sugar, control of DNA replication and more. These gardens are called "the gardens of the household".
The genes of the second type are unique genes, which are activated in a different format in different tissues. The gene responsible for hemoglobin production is active in the red blood cells; In the cornea, the gene that produces the protein that determines eye color is active; In the liver, the genes responsible for liver functions are active, and all other genes are silenced. How does this mechanism work? How is the selective activation of the unique genes done, and who makes sure that the genes of the household are always active?
Prof. Haim Sider, from the Department of Cell Biochemistry at the Hebrew University School of Medicine, has been researching these questions for 25 years, and during his research discovered the mechanism responsible for the selective activation of the genes. The person responsible for this is a small chemical group called the "methyl group". Methyl groups attach to the DNA, "locking" it in place
The attachment - and the genes in that area are silenced. The genes that are blocked are those whose activity is not required in this or that tissue; On the other hand, the genes necessary for the activity of the tissue remain free, and likewise the genes of the household. The genome as a whole is thus largely locked.
The DNA locking mechanism exists only in mammals. Its activity model is not inherited. The fertilized egg, obtained from the fusion of a sperm cell and an egg, contains DNA, most of which is locked; Only the genes of housekeeping and the unique genes of the gametes are not locked. Very early in the development of the embryo (in the first week in humans) all the locking is erased, and the embryo begins its life like a smooth board.
During implantation in the uterus, the genes are locked again. The entire genome is automatically locked, except for the household genes. These genes carry special markers that prevent them from being locked. The markers differentiate between the genes of the household and the genes unique to the different tissues, which get their role later, when they differentiate into tissues and organs. During differentiation, different genes are unlocked depending on the role they receive in the tissue.
When the liver, for example, begins to develop, the lock is released in all the genes responsible for the production of the proteins that participate in the functions of the liver. This also happens in other tissues.
The mechanism of locking and releasing the genes, which allows monitoring of their function, was discovered by Cedar and his group in studies done in cell culture. In these studies, they were able to artificially block various genes in the cells, but it has not been proven that the blocking of the genes actually plays a role in a living system. Without the proof, the explanation remains only a theory.
The theory was confirmed in a study conducted by Dr. Zehava Siegfried and Cedar's team and published three years ago in the journal "Nature." Genetics The researchers transferred the marker that distinguishes the housekeeping genes to the gene responsible for creating the hemoglobin protein in mice. Hemoglobin is created naturally in the blood cells only. "If the theory is correct, the marker of the genes for housekeeping should have ensured that the gene coding for hemoglobin was not blocked in embryonic development, so we expected it to be expressed in all the tissues of the mice and not just in the blood cells," says Seder. Indeed, the researchers discovered a strong activity of the gene coding for hemoglobin not only in the blood cells but also in the liver, kidney, spleen, brain and other tissues. In all these places the garden is never active.
"In this study, we discovered for the first time that the gene locking theory is indeed true," says Cedar. "But important questions, for example how the lock works and how exactly it prevents the activity of the garden, remained open." These questions were also investigated by Cedar's group, with the participation of doctoral students Tamar Shamshoni and Jenmin Chang and with the support of the National Science Foundation. "It is known today that actually the one who regulates the activity of the gene is its protein coat," says Cedar. "The DNA does not sit naked in the cell nucleus, but is packed inside a protein structure. We discovered that the locking of the genes by the methyl groups affects the change of the protein packaging".
In the study, published last month in the journal "Nature Genetics", the researchers created two groups of mice. In mice from one group, they "locked" the gene that codes for hemoglobin; In the second group the garden was not locked. At the same time, the researchers examined the protein packaging structure of the gene. "In the locked garden we discovered that the packaging was closed, but in the garden that was not locked we discovered that the protein packaging was open and therefore allowed the garden to express itself," says Cedar. "The locking of the genes in mammals therefore gives an order to the protein packaging to be open or closed, and this is what determines the expression of the gene.
In our experiments we have shown that the expression of any gene can be controlled by unlocking it. Today we are able to take a complex organism like a mouse and give it instructions on how to develop."
The mechanism of locking and releasing the genes explains the first stages of development of the embryo - the differentiation of the cells through the silencing of the genes that are not necessary for the tissue's function. But the study of the mechanism may have consequences not only for understanding the basic activities of the cell, but also for research in the field of cancer. In recent years it has become clear that cancer cells contain many genes that undergo a lock that prevents their activity. In some cases the lock stimulates the cancer process. "The hope is that understanding the locking mechanism and neutralizing it will allow us to prevent or change the locking and in this way fight the cancer process," says Cedar. "It is possible that the ability we have developed to control the process will help with this."
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