Faced with sudden changes caused by environmental stimuli and stress, cells too are called upon to make quick decisions. Thus, when there is a crisis – from the Greek krisis “choice” – cells must adapt their own normal genetic programming “reining in” the power of their engines, like ships suddenly needing to change course. The man who, for the first time, discovered how this happens at a global level in the genome is Valerio Orlando, researcher at the Telethon Dulbecco Institute who works at the Santa Lucia Foundation in Rome. Cells react to a crisis by directly modulating the activity of the genes thanks to RNA interference, a mechanism greatly preserved at evolutionary levels that, in 2006, resulted in its discoverers Craig Mello and Andrew Fire winning a Nobel Prize. This study, financed by Telethon and the Italian Association for Cancer Research and sponsored by the Foreign Ministry (listed among Italian-Japanese projects of great importance) was published in Nature* magazine.
RNA – the acronym for ribonucleic acid – is a molecule similar to DNA that carries out many tasks in cells, among them acting as a messenger. Starting with DNA, the cell produces filaments of RNA that act as a “mould” for their translation into proteins. RNA interference is a mechanism common to almost all living organisms, even simple ones such as yeast, which evolved firstly to protect cells from viruses, the main source of extraneous RNAs. Cells recognize these molecules as extraneous, put themselves in a state of alert and reduce the molecules to smaller pieces to eliminate them, thereby avoiding production of viral proteins. In the course of evolution this mechanism has also been adopted to repress the production of cellular proteins not needed at any given moment, thereby controlling proteic synthesis in a very refined manner. Small RNAs produced by the cell recognize specific parts in the “messenger RNA” and thus decide their destruction.
Contrary to what was believed, it was recently discovered that only 5% of the genome produces information that is later transformed into proteins. In fact, most of the RNAs produced appear to act at a higher level than the DNA with mechanisms that researchers describe as “epigenetic” and that allow cells to preserve their identity over time. Studying these mechanisms is important for understanding not only how a cell acquires its distinctive characteristics, but also how the loss of this identity can lead to pathological states such as, for example, tumours and degenerative diseases.
«It was thought until now that the regulation of RNA levels, and therefore proteins, took place in the cytoplasm, the cell compartment in which messenger RNA is converted into proteins- explains Orlando -. In this study we have proved for the first time that this also takes place in the nucleus, where the DNA is situated. This is a totally new ‘global plan’ for gene regulation, which researchers from all over the world have been looking for, for a very long time. According to this plan, when there is a ‘crisis’ such as, for example, sudden changes in temperature and available nutrients, or changes in the course of development, the cell exploits the mechanisms that produce small RNAs inside the nucleus to directly inhibit RNA production at the source and thereby adapt to environmental conditions».
«Our results, obtained by studying fruit fly cells, are extremely interesting – explains Davide Corona, Telethon researcher at the University of Palermo who took part in the study -. In diseases caused by an excessive or reduced production of certain proteins, these small nuclear RNAs could in fact be used to modulate gene behaviour in a stable manner, regulating the amount of protein produced, without necessarily intervening on the genetic defect responsible for the pathology».
So as to acquire in-depth knowledge of this previously unknown role played by small RNAs, researchers are now also at work to try and understand in detail their mechanisms in human cells. Orlando concludes, «The discovery of this mechanism is a fundamental step forward in understanding how small RNAs can be used as treatment operating at an “epigenetic” level instead of at the genetic level».
*Cernilogar F., Onorati, M.C., Khothe G., Burroughs M., Parsi K.M., Breiling A., lo Sardo F., Saxena A., Miyoshi K., Siomi H., Siomi M., Carninci P.,Gilmour D., Corona D. and Orlando V. “Chromatin-associated RNA components contribute to transcriptional regulation in Drosophila” Nature November 2011-10-28