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When the genetic messenger discovers independence

Why does the cell need a gene control mechanism through changes in messenger RNA?

Illustration: pixabay.
Illustration: pixabay.

DNA is sometimes compared to an instruction book, but unlike ordinary books, the information in this "book" may change over time. Chemical tags attach to DNA in millions of places, changing the genetic instructions. Many studies have been devoted to these tags over the years, but it turns out that changes may occur in the genetic information even after the message has been "sent": the chemical tags can attach to the molecular messengers called messenger RNA, those transient molecules that transmit the recipe for assembling proteins from DNA To the cellular machines that build the proteins. In the study thatRecently published in the scientific journal Nature Scientists from the Weizmann Institute deciphered the mechanism of action of one of the possible changes in messenger RNA, and discovered that it can change the genetic message from end to end.

More than 100 changes may occur in messenger DNA, but only five are currently known to science. Moreover, only in recent years have scientists recognized the enormous importance of these changes, which actually constitute a genetic control mechanism, with the ability to increase or decrease gene expression, or even activate or silence this or that gene. As a result, they play a role in most biological processes, and may be involved in a wide variety of diseases.

In the new study developed by Dr Shraga Schwartz from the Department of Molecular Genetics, together with his colleagues, a new method for studying changes in messenger DNA. His group applied the method to one of the changes known as m1A: the attachment of a methyl group-type chemical tag to a certain component of messenger RNA - the nucleotide A. The scientists created maps showing the appearance of the change in the entire genome, and identified its location with unprecedented precision. They also found which enzymes cause the m1A change to occur in messenger RNA. In fact, the scientists discovered that although m1A is much less common than previously thought, on the other hand, it has the power to completely change the way the message conveyed by messenger RNA is "received". This change causes a cell to "ignore" the message that the DNA is sending, and the consequences of this "ignoring" are far-reaching. For example, in an embryo with only eight cells, m1A marks an essential gene in the mitochondria, the "powerhouses" of the cell, and thus probably serves as a kind of "switch" that changes the way in which the embryo produces the molecular fuel that enables its existence. It seems that this "switch" is the one that causes the fetal cells to stop breaking down glucose as a source of energy, and instead start to produce energy from the mitochondria.

Computer display of genetic "letters" – A, C, G and T – in the segment of messenger RNA molecule containing the m1A change. The letter A, where the change occurs, is indicated by an arrow. Source: Weizmann Institute magazine.
A computer display of genetic "letters" - A, C, G and T - in the segment of the messenger RNA molecule containing the m1A change. The letter A, where the change occurs, is indicated by an arrow. Source: Weizmann Institute magazine.
A computer display of genetic "letters" - A, C, G and T - in the segment of the messenger RNA molecule containing the m1A change. The letter A, where the change occurs, is indicated by an arrow

These findings shed new light on cell life, and may help in the study of diseases in which energy production in cells goes wrong. For example, cancer cells, unlike most healthy cells, generate energy by breaking down glucose, which helps them survive in the low-oxygen environment of the malignant tumor.

But why does the cell need a gene control mechanism at all through changes in messenger RNA? What advantages do these changes have over other control mechanisms, including those that produce or destroy entire messenger RNA molecules? "Probably different types of gene control have developed during evolution, because each of them confers advantages in different situations," says Dr. Schwartz. "It is possible that the mutations in messenger RNA are most suitable for rapid changes in gene activity; For example, increasing or decreasing this activity in response to a certain stimulus".

The method for studying m1A, which was developed in Dr. Schwartz's laboratory, may advance the study of other changes in messenger RNA. It can also contribute to the understanding of diseases in which there are mutations in the enzymes that produce the changes, including cancer, severe obesity, and degenerative brain diseases.

From the right: Dr. Sharga Schwartz, Dr. Aldama Shesh-Chen, Dr. Modi Safra and Dr. Ronit Nir. Blame the messenger. Source: Weizmann Institute magazine.
From the right: Dr. Sharga Schwartz, Dr. Aldama Shesh-Chen, Dr. Modi Safra and Dr. Ronit Nir. Blame the messenger. Source: Weizmann Institute magazine.

The research group included Dr. Modi Safra, Dr. Aldama Shesh-Chen, Dr. Ronit Nir, Dr. Dan Bar-Yacob, Roni Winkler and Aharon Nachshon. The research was conducted in collaboration with Dr. Noam Ginosar, also from the Department of Molecular Genetics, Dr. Matthias Erlcher from the Medical University of Innsbruck, and Dr. Walter Rossmannit from the Medical University of Vienna.

"Enjoys research more"

Shraga Schwartz even planned to be a doctor. He graduated with honors with a bachelor's degree in medicine at Tel Aviv University, and was accepted to the MD-PhD track: medical studies combined with a PhD in research. But when he had only one year left to complete his medical studies, he decided to change direction and choose science. "There is added value to practicing both medicine and research, but I realized that I enjoy research much more," he says. After a year of post-doctoral studies in the laboratory of Prof. Rotem Shurk, in the department of molecular genetics of the Weizmann Institute, Dr. Schwartz continued his research at the Broad Institute of Harvard University and the Massachusetts Institute of Technology. He joined the faculty of the Weizmann Institute of Science in 2015. In 2017 he won a grant for outstanding young researchers on behalf of EMBO - the European Organization for Molecular Biology.

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