Biological control and proper administration

Weizmann Institute of Science scientists reveal the hierarchical mechanisms that oversee the function of the genetic load, and determine the genomic organization

Not everyone appreciates it, but bureaucracy is a necessary mechanism for maintaining the proper functioning of society: supercommittees coordinate the work of government ministries, which in turn supervise the activities of divisions, departments and individual employees, when investigative committees are appointed to investigate failures. All these create a branched organization, with complex interrelationships. The living creatures have also developed, during evolution, a multi-level hierarchy that supervises the activity of their genetic load. This genetic control network creates a strict and sensitive mechanism, responsible for activating the right genes at the right time.

The low level of the cell's bureaucracy includes the "transcription factors", which are proteins that supervise the transcription process, that is, the production of RNA molecules according to the information stored in DNA. The molecule created in this process, called messenger RNA, exits the cell nucleus into the intracellular space, where the protein factories - the ribosomes - are located, which translate the genetic information and create the proteins based on it.

A bureaucratic chain of control processes accompanies this process throughout, so that the production of proteins can be stopped at any of the stages along the way. One of the critical factors is a group of microRNA molecules (microRNAs). These molecules, which have only recently been identified, consist of very short sequences of RNA, and their role in the control system is to silence the messenger RNA. The microRNA molecules identify a target site on the messenger RNA, cling to it thanks to matching the base sequence of the two molecules - thus stopping the protein production process.

Dr. Yitzhak Papel from the Department of Molecular Genetics at the Weizmann Institute of Science, Prof. Moshe Oren from the Department of Molecular Biology of the Cell, and research students Reut Shelgi and Daniel Leiber sought to understand the "organizational structure" of the control network, which includes the genes, the transcription factors and the micromolecules - RNA They analyzed data of the interrelationships between thousands of genes, hundreds of microRNA molecules and hundreds of transcription factors. Using complex computer software, they tried to determine the structure of the complete network, characterize its main features, and locate "secondary structures" embedded within the general network structure. These "repetitive motifs", combinations of components that appear repeatedly in the network, have given scientists important clues as to how genomic organization works. Their findings were recently published in the PloS Computational Biology journal.

The scientists managed to discover two types of structures in the network. The first group includes two microRNA molecules that work
jointly to silence a gene or group of genes. Dr. Pepper compares buildings of this type to advanced automatic systems: "This is similar to a system that is able to monitor two different parameters, such as an automatic cooling system that checks temperature and humidity, and activates the engine only when both are high. Similarly, it is possible that integrated microRNA structures allow cells to make decisions based on more than one type of information."

A second set of constructs included transcription factor and microRNA pairs. In some of these structures the transcription factors were under the control of the microRNA, and in others the order of control was reversed, and the transcription factors controlled the activity of the microRNA. In some pairs the control was mutual, and worked in both directions. Later, the scientists tested the significance of their findings in tissues and organs, and discovered that a high level of microRNA of a certain type is accompanied by a high level of the corresponding transcription factor in that tissue or organ. The scientists believe that the pairs consisting of a transcription factor and microRNA are of great importance in development processes. "Development depends on the activation of groups of genes in precise timing, which may require additional levels of control," says research student Reut Shelgi. "In order to enable the close coordination between gene activation and gene silencing, it is possible to create a sort of delay mechanism, which shuts down the protein production line within a calculated period of time after the start of its activity."

Just as following notes and memos may reveal the centers of power in a bureaucratic organization, so knowing the map of the interrelationships between the various components of the genetic control network will help scientists understand the function of the genome. These findings may promote many studies in different fields, mainly in developmental biology, as well as studies dealing with diseases in which groups of genes are involved.

Short

Most "gene silencing" (that is, stopping the process of making a protein according to a certain gene), which occurs after the end of the transcription phase, is not caused by proteins, but by RNA. This surprising discovery earned Andrew Pierre and Craig Mello the Nobel Prize in Physiology or Medicine for 2006. In fact, the human genome mapping and decoding project showed that only about one percent of the DNA in the human genome codes for protein production. A large part of the remaining 99 percent is transcribed into RNA molecules called by the general name "non-coding RNA". These molecules participate in the construction of important cellular structures, such as the ribosome, or in the "bureaucratic committees" that control the various activities in the cell. These controlling factors include small RNA molecules that interfere in various processes (small interfering RNA - siRNA), and microRNA. To date, about 500 different microRNA molecules have been identified, but scientists believe that their total number reaches about a thousand, and that they affect the expression of thousands of genes.

abbreviated dictionary

* MicroRNA (microRNA): short, single-stranded RNA molecules, which control the activity of various genes by silencing messenger RNA after its transcription.

* Messenger RNA (mRNA): a single-stranded molecule that contains the genetic instructions for protein production. Serves as a guide for the production of proteins in the ribosome.

* RNA interference (RNAi): stopping the expression process of a certain gene by blocking the process or breaking down messenger RNA.

* Small interfering RNA (siRNA): double-stranded RNA molecules, which interfere with gene expression.

* Transcription factor: a protein that is responsible for driving the copying process of the DNA code into an RNA molecule.