Scientists find new roles for old RNAs

The loss of small nucleolar RNAs is associated with a number of diseases, including Prader-Willi syndrome, in which victims have insatiable appetites, and several forms of cancers.

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July 24, 2016 00:09
4 minute read.
The Hebrew University

The Hebrew University. (photo credit: Wikimedia Commons)

 
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An international research team that included Hebrew University of Jerusalem researchers have discovered unexpected functions of small nucleolar RNAs (snoRNAs) that explain the cause of some diseases. The research, led by Prof. Stefan Stamm from the University of Kentucky and HU Prof. Ruth Sperling, was recently published in The Proceedings of the National Academy of Sciences.

The loss of small nucleolar RNAs is associated with a number of diseases, including Prader-Willi syndrome, in which victims have insatiable appetites, and several forms of cancers including multiple myeloma and malignant tumors of the breast and prostate. Also, genetic duplications of some snoRNAs could play a role in autism.

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However, it has not been clear how the change in snoRNA expression could lead to these diseases.

Hereditary information is stored in DNA, which is accessed through an intermediate form, called RNA. To make proteins that function in cells, a “photocopy”of the stored genetic information – called precursor messenger RNA – (pre-mRNA). is made. From these precursor molecules, the important information containing the blueprint for proteins has to be extracted through a process termed splicing, where parts called introns are cut out.

The remaining parts, called exons, are pasted together to generate messenger RNA (mRNA). This can be compared to the splicing of movie film in which excess images are cut out and the remaining parts are joined together to create a seamless movie.

Most mammalian pre-mRNAs are multi-intronic and can be spliced out in different combinations. Therefore, an important major mechanism that is at work for building complex organisms and organs is alternative splicing, in which different combinations of alternative splicing a single gene can code for multiple proteins.

The misregulation of the alternative splicing process contributes to numerous diseases, including cancer.



Using RNA sequencing and molecular biology techniques, the researchers found that often snoRNAs not only modify ribosomes, but can also regulate alternative splicing, thus inhibiting the generation of wrong protein variants. These new functions can explain the role of snoRNAs in human diseases, as upon their loss the formation of wrong protein variants can no longer be prevented.

“This research helps us to understand the unexpected dual role of snoRNAs in gene regulation. It further points to the important role played by small non-coding RNAs in alternative splicing, which is a major contributor to the diversity of the human proteome, and defects in which result in numerous diseases including cancer. With further research in this area we may be able to design new therapies against human diseases,” Sperling concluded.

SHEBA GETS NEW D-G Prof. (Brigadier-General res.) Yitzhak Kreiss has become director-general of the country’s largest hospital, the Sheba Medical Center at Tel Hashomer. The internal medicine specialist and former Israel Defense Forces chief medical officer comes to fill large shoes – those of Prof.

Zeev Rotstein, who served the hospital for the last 36 years and for the past 12 years was its director-general. .

Kreiss, a graduate of the Hebrew University Medical Faculty, also has a master’s degree in health administration from Tel Aviv University and in public administration from Harvard University. Kreiss is married and has three children. He has much experience in dealing with medical catastrophes and giving humanitarian aid around the world. As such, he brought IDF assistance to victims of the Haifa earthquake, wounded from the Syrian civil war and people hurt in the typhoon in the Philippines.

DOWN THE FRONT Researchers at Haifa’s Technion-Israel Institute of Technology have made new discoveries about the development of the body’s frontal midline around which the heart, lungs and digestive system are formed. They were recently published in the journal Developmental Cell.

The study was carried out by Professor Tom Schultheiss and doctoral student Alaa Arraf from the Technion’s Rappaport Faculty of Medicine in conjunction with Andreas Kispert from the Institute of Molecular Biology at Hannover Medical School in Germany.

According to Schultheiss, “in contrast to the dorsal midline and spinal column, whose aspects have been studied extensively, the process of development of the frontal midline is not clear. This is despite the importance of this line, on and around which the heart, navel, genitals, aorta, digestive system, sternum, bladder, liver, pancreas, lungs and more are formed.

The development of the dorsal midline precedes the development of the frontal midline, Arraf explained.

“Therefore it is important for the frontal midline to develop in coordination with the dorsal midline. Disruption of this process causes a discrepancy between the back area and the abdominal area and may impair the development of organs such as the heart and lungs and even lead to death of the organism in some cases.”

In the current study, the researchers examined the cellular and molecular mechanisms responsible for the formation of the frontal midline in the early stages of embryonic development. One of the key factors controlling this process is the BMP (bone morphogentic protein) gene. “It turns out that control of BMP from a central source (the notochord) enables precise coordination and timing in the formation of the frontal midline. Unbalanced expression of BMP will result in the shifting of the frontal midline, which can cause subsequent problems in the development of the internal organs in the abdomen and thorax.

“The practical purpose of these fields is to create tissue in the lab that can be used to repair damaged organs,” explained Schultheiss.” To do this, we must have a thorough understanding of tissue formation during the natural process of embryonic development. Therefore, we are investigating the formation of organs in the earliest stages, in which the embryonic cells acquire specific properties that are suitable for the target tissue (such as bone and skin), as well as the next stages in which the various cellular components combine to form a functioning organ.”


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