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The small directors in the cell

They have been overlooked for quite a long time, despite the fact that they constitute a large part of the genetic material in many organisms. Biologists are gradually discovering that bacteria as well as human and plant cells need them for proper function. Prof. Dr. Wolfgang Hess and his team at the Institute of Biology III at the University of Freiburg have been focusing on them for a number of years – we are referring to non-coding RNAs. The Freiburg researchers found that these small molecules regulate the energy and health metabolism of bacteria. But it is possible that they may be able to do a great deal more.

Only about five percent of the human genome consists of genes. What is the rest needed for? Over the last few years, scientists have found growing evidence that points to the existence of DNA areas between the genes of all groups of organisms, which are also transcribed into RNA. But these areas are not the blueprint of enzymes, signalling proteins or cell components. In fact, these small RNA segments, also referred to as non-coding RNAs, control many vital cell processes on the molecular level. The genome of cyanobacteria also has such regions, which are, at least superficially, silent. “Using molecular biology methods, we have discovered areas in the genome of these bacteria that are transcribed into non-coding RNAs,” said Prof. Dr. Wolfgang Hess from the Department of Genetics and Experimental Bioinformatics at the University of Freiburg’s Institute of Biology III. “In subsequent experiments, we found that these molecules regulated the energy supply of the bacteria, for example.”

Complex research objects

The cyanobacteria communities in different water samples are a “colourful” mixture. © Prof. Dr. Wolfgang Hess

Cyanobacteria are very old organisms. They have been on earth for at least 2.5 billion years. They are fascinating for many reasons. Many millions of years ago, they developed the ability to produce energy from sunlight. Photosynthetic mechanisms help them produce oxygen and biomass from CO2 and water. With their ability to produce oxygen, they filled the earth's ‘stuffy' atmosphere with the gas that animals and other breathing organisms require for life. The majority of researchers nowadays assume that a former cyanobacteria representative was incorporated into a larger cell. According to this so-called endosymbiotic theory, this incorporation led to the first plant cells with photosynthetic chloroplasts. "Nowadays, cyanobacteria have become popular research objects because they have a broad spectrum of exotic metabolic pathways," said Hess. They are not only seen as organisms that swallow CO2, some of them can also produce oils and alcohols. And this might make some people immediately think of biodiesel.

Cynanobacteria of the genus Fischerella form multicellular colonies. © Prof. Dr. Wolfgang Hess

Cyanobacteria are fascinating research objects for Hess and his team. The bacteria can quite easily exchange entire gene packages with each other, which suggests that the cyanobacteria populations in the sea are more like a metaorganism with a metagenome, since no single individual has at any point in time all the genes that make up the species as a whole. Different gene combinations are distributed across all the different organisms of the species. And then there is still the non-coding RNA. Cyanobacteria are excellent experimental organisms, they are easy to cultivate in the laboratory, they reproduce quickly and they incorporate foreign DNA, available in their surrounding environment, into their own genome. This makes them easy to manipulate.

The Freiburg researchers discovered a short DNA sequence in the Synechocystis blue algae, which is located on the opposite strand of a particular gene. This sequence is the blueprint for a non-coding RNA, whereas the gene on the opposite strand contains the information of a protein that is part of an alternative light-collecting complex. This protein apparatus is expressed under stress (for example when iron concentrations in the sea are too low) and catches light beams that are subsequently turned into sugar, i.e. biologically usable energy.

Versatile research objects

Synechocystis blue algae © Prof. Dr. Wolfgang Hess

"We found that the short RNA fragment binds to the RNA transcript of the gene," said Hess. Since the two DNA sequences are located opposite each other, the two RNAs are also complementary and can therefore pair with each other quite well. However, the double strands thus formed are very instable and are rapidly degraded. This is how the non-coding RNA controls the amount of protein in the cell. "The RNA controls one, if not the most, basic process of life," said Hess highlighting the fact that the RNA consists only of 170 nucleotides.

Another discovery, made in 2007, confirms the huge effect of the small pieces of RNA: Bacteria that are attacked by certain viruses (i.e. bacteriophages) and which survive the attack, incorporate fragments of the viral genome into their own genome. These short sequences are then flanked by DNA from which non-coding RNA is produced. The resulting RNAs therefore have the signature of a certain virus. They form big defence complexes with proteins and serve as probes. If the known virus re-enters the cell, its genetic material binds to the complementary RNA pieces and the complex chops it into pieces. "It resembles an adaptable immune system," said Hess. Some bacterial genomes have large viral sequence batteries that are flanked by non-coding RNAs. It is rather like an immunological archive that can be consulted as soon as a virus attacks the bacteria. "We are now investigating how the viral genome becomes part of this genetic archive when the initial attack occurs," said Hess.

The researchers are also using modern automated systems biology methods, which are currently being established at the Centre for Biosystems Analysis (ZBSA) in Freiburg, to search for more unknown RNAs in the genome of their experimental objects. Initial experiments have already provided the researchers with several hundred different candidates. It is worth noting that about 80 such RNAs are known in the well-known E. coli bacteria. "If bacteria with about 4000 genes also have hundreds of non-coding RNAs, then it can easily be imagined that quite a few things have to be regulated," said Hess. One thing seems quite clear. To reduce the behaviour of a cell to the effect of their proteins increasingly seems to be rather a naïve idea.

Further information:

Prof. Dr. Wolfgang R. Hess
Genetics & Experimental Bioinformatics
University of Freiburg
Institute of Biology III
Schänzlestraße 1
79104 Freiburg
Tel.: +49-(0)761/203-2796
Fax: +49-(0)761/203-2601
E-mail: Wolfgang.Hess (at) biologie.uni-freiburg.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/the-small-directors-in-the-cell