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The unlikely masters of gene expression
9/6/16
The transcription factors involved in coordinating the transcription of DNA into messenger RNA have been
known for some time. Recent studies have shown that their role is not limited to these early stages of gene
expression. In a study published in Nature Structural & Molecular Biology, a team of researchers led by
Franck Dequiedt has highlighted the involvement of transcription factors in the decay of messenger RNA
outside the cell nucleus.
DNA contains all the information necessary for the healthy functioning of an organism. But holding information
is not enough in itself. This information must be correctly transmitted to the different actors that are involved
at cellular level so that it can be translated into concrete action. To go from DNA to the proteins that execute
these concrete actions, a series of stages is necessary. This is called gene expression. In the "Protein Signaling
and Interactions" Laboratory of the Molecular Biology of Diseases Unit of GIGA at the University of Liege,
Franck Dequiedt has focused his interest on the molecular mechanisms that control gene expressions. "We
are studying the molecular actors that enable the proteins to express themselves at certain times", explains
Franck Dequiedt. For many years, the model that has prevailed and that has been taught to students is one
which describes gene expression as occurring in a series of successive stages: synthesis of pre-messenger
RNA from DNA, maturation into messenger RNA, export to cytoplasm, passage through the ribosomes and
translation into protein. For many years, this has been represented in linear form where the stages occur one
after the other", explains the researcher. "But we are becoming increasingly aware that this does not reflect the
reality. Recent studies show that there are connections between the different stages". In a study published in
Nature Structural & Molecular Biology (1), in collaboration with researchers from America and ULB, Franck
Dequiedt's team has identified one of the significant connections.
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Reflexions, le site de vulgarisation de l'Université de Liège
Constantly evolving knowledge
One of the first stages in gene expression is called transcription. It occurs in the cell nucleus and consists
of the transcription of areas coding DNA into RNA molecules. It partly involves the production of a copy of
the part of the DNA concerned so that this remains intact. This copy is mobile and readable by the translation
machinery that leads to the production of proteins at the end of the process. "The transcription stage is
principally coordinated by the transcription factors", explains Franck Dequiedt. "It is they that make it possible
to decide when, where and to what extent the genes are expressed". Knowledge about the role played by these
crucial actors was previously limited to the early stages of gene expression. We knew they were important for
the recruitment of RNA polymerase, an enzyme that catalyzes the reaction of transcription, as well as for the
triggering of the transcription", explains the Director of the Molecular Biology of Diseases Unit of GIGA. "But in
a system where the stages of gene expression overlap to a great extent, studies have given clues about the
fact that transcription factors could act on other things such as the speed of transcription or the splicing which
enables the RNA to be "cleansed" of its superfluous parts". These discoveries about the increased role of the
transcription factors are important but have not revolutionized the "status" of the transcription factors because
these stages always occur in the cell nucleus. What Franck Dequiedt and his colleagues have shown in their
recent study is that the transcription factors, in this case ERG (E-26 related gene), can also influence later
stages of gene expression which occur in the cytoplasm, that is to say, outside the nucleus. "It was difficult to
imagine that the transcription factors could cross the nuclear membrane", says the researcher.
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The bind between synthesis and decay of messenger RNA
Under the microscope of Franck Dequiedt's team: a family of transcription factors called ERG, chosen for their
prototypical character. In fact, they respond very well to the typical criteria for transcription factors: they have
an area for recognizing DNA, they bind to well-defined DNA sequences, they bind to promoters, interact with
the machinery that initiates transcription etc. "We have shown that, as well as the role of coordinator of all
stages of transcription, these transcription factors can be found in the cytoplasm associated with mature RNA,
ready to be translated, and they coordinate the decay of this RNA, the specialist explains. For a very long
time, the scientific world was content to study RNA synthesis, on the understanding that the organism either
produced or did not produce RNA in accordance with its protein requirements.
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…
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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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Reflexions, le site de vulgarisation de l'Université de Liège
(1) Xavier Rambout, Cécile Detiffe, Jonathan Bruyr, Emeline Mariavelle, Majid Cherkaoui, Sylvain Brohée,
Pauline Demoitié, Marielle Lebrun, Romuald Soin, Bart Lesage, Katia Guedri, Monique Beullens, Mathieu
Bollen, Thalia A Farazi, Richard Kettmann, Ingrid Struman, David E Hill, Marc Vidal, Véronique Kruys,
Nicolas Simonis, Jean-Claude Twizere & Franck Dequiedt. The transcription factor ERG recruits CCR4NOT to control mRNA decay and 2 mitotic progression, Nature Structural & Molecular Biology, juin
2016
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