Researchers discover that temperature controls genetic messengers

Alternative Splicing, the mechanism that enables a gene to codify different proteins depending on the cell's needs, still hides many secrets. It has transformed the initial theory of "one Gene, one protein" but its control strategy is still largely a mystery.

A team of researchers at the Spanish National Research Council (CSIC) has discovered a new control strategy: temperature. The team, led by Josep Vilardell, an ICREA researcher at the CSIC's Molecular Biology Institute of Barcelona, has discovered that temperature affects RNA's structure and thereby, controls which parts of the genetic sequence it uses.

Also involved in this discovery, which is published this week in the journal Molecular Cell, were Eduardo Eyras, ICREA researcher and Mireya Plass, who are both researchers at the Computational Genomics Group of the Biomedical Computing Research Unit (GRIB) at UPF-IMIM, as well as members of the Centre for Genomic Regulation (CRG) Research center affiliated to UPF.

Hiding Intronic signals

Scientists have been trying for a long time to find out how the spliceosome - the molecular machinery responsible for splicing, works to generate an mRNA with the potential to codify the correct protein.

During this splicing operation, the spliceosome selects internal fragments in the sequence, in a process in which it cuts genetic sequences of the RNA at very specific points: the end of the introns. It subsequently splices these fragments together to generate a new mRNA.

Errors in splicing can be lethal. According to Josep Vilardell, the question is "How it does it correctly recognize the splicing at the end of the introns? We have tried to find an answer in the Saccharomyces cerevisiae yeast. It has a small and well-characterized genome, with a small number of introns. This helped us to simplify the problem."

Researchers have found that in a narrow range of temperatures, between 23 to 37 degrees centigrade, some yeast RNAs change their structure, hiding or showing  particular segments in each case. Since RNA uses all the accessible cut places but not the hidden ones, the result is that the same intron is recognized in a different way, which finally leads to two different proteins.

Scientists have shown that the temperature and the flexibility inherent in RNA provide "an autonomous control strategy for RNA processing. We knew that temperature affects the structure of RNA, but not that it affected the function of the splicing by small structural changes in the RNA substrate."

What are the consequences of this alternative process? Vilardell explains that "in the yeast's gene where it has been detected, the hypothesis is that it affects the stability of the protein or its interaction with other molecules."

Now, he adds, "we are very interested in finding out what happens in more complex organisms. There's no reason to think that this strategy doesn't occur in mammals, in which the effects could be more relevant from a health perspective."

There are situations in which our organism varies its temperature, and it is possible that a specific type of splicing happens under these conditions. Perhaps the most obvious example is in fever, as pointed out by Josep Vilardell. It is possible that some RNAs have acquired the ability to respond to subtle temperature variations by means of small structural changes.

Some biological processes need a specific temperature (the creation of spermatozoids requires less than 37 degrees, for example) and the optimum gene expression may require an adequate fold of the specifically expressed genes' RNA.

Another equally important scenario focuses on the need for quick adaptation to sudden changes in temperature. "This implies the generation of new isoforms of proteins, as well as RNA which has lost its encoding ability, to avoid the synthesis of counterproductive proteins under those conditions. Our data shows that this quick response may be transmitted by the structure of the RNA we process itself."