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The unlikely masters of gene expression
9/6/16

What the scientific world missed in terms of this model was that once this RNA had fulfilled its role, it needed to be eliminated so that it would not be used to produce proteins. “During all this time, it was believed that RNA decay was limited to the elimination of aberrant RNA, that is to say RNA containing errors following transcription. But for the last ten years or so, we have understood that the specific decay of RNA is an integral part of the arsenal of the cell which makes it possible to precisely control the levels of proteins”, continues the researcher. Based on studies carried out on yeast and transcriptomic studies, we know today that there are links between the synthesis and decay of RNA but we had not yet satisfactorily identified a protein that could connect the two processes. But that was before the present study…

EGR nucleus

Between factors and messengers, a matter of life and death!

The researchers from Liege and their colleagues have identified a class of proteins that is involved both in the birth and death of messenger RNA. “We find the transcription factors at the two extremes of the messenger RNA cycle”, says Franck Dequiedt. In addition, the scientists have demonstrated that the ERG transcription factors control the transcription of certain genes as well as the decay of messenger RNA resulting from these genes. “In most cases, the decay of messenger RNA is controlled by the same transcription factors as those that triggered their synthesis”, the researcher points out. “Which is very interesting for the cell because, with a reduced number of proteins, it can also control the synthesis and decay of messenger RNA”. 

But these two processes occur in different cellular compartments: one in the nucleus and the other in the cytoplasm. How do the transcription factors cross the cell membrane to bring about the decay of messenger RNA in the cytoplasm? “We have not formally demonstrated this, but we think that the transcription factor somehow jumps onto the messenger RNA during synthesis. Once it is ready, the RNA coupled with proteins takes on a particular form under which it crosses the nuclear membrane. The transcription factor is incorporated into this complex and exported into the cytoplasm where it takes charge of the decay of messenger RNA whose synthesis it has controlled”, explains Franck Dequiedt. The researchers from Liege are currently working on verifying this theory. In addition, as the transcription factors are present at the birth and death of RNA, we can reasonably suppose that they are present for the entire life of the RNA. They could potentially coordinate all the intermediary stages between the synthesis and decay of RNA. This is also a research subject in Franck Dequiedt’s team today. “We are in the process of showing that they control the splicing, export and probably also the translation of RNA”

The ERG transcription factors and cancer 

Therefore, the transcription factors are not only small discreet hands that enable the triggering of RNA synthesis. They are also the veritable masters that coordinate the different stages that result in an efficient and reactive control of gene expression. These discoveries are very important, particularly given the fact that we know that in order to understand the role of a transcription factor, scientists prevent its expression and are making transcriptomic analyses.  “We then look inside the cell, in the tissue or in the organism to see what variations occur in the messenger RNA levels of the different genes. And we have been able to deduce which genes are controlled by the transcription factor in question”, explains Franck Dequiedt. “Our discoveries show that we cannot stop there. If we prevent the expression of a transcription factor, for an entire series of genes the overall levels of RNA will not change because RNA synthesis and RNA decay of these genes will diminish or increase both of them”.  This therefore means that we have to be very vigilant during the use of such methods in the case of transcription factors and to be conscious of the fact that they have other roles that just controlling the levels of RNA produced. 

Finally, the transcription factors of the ERG family are oncogenic. “They have been clearly identified as a causal factor in cancers such as prostate and leukemia etc. And the explanation of their oncogenic role is currently limited to their control of the transcription of certain genes. But their oncogenic role could be due to their role in messenger RNA decay or splicing or other functions as yet unknown”, concludes Franck Dequiedt. 

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