The unlikely masters of gene expression
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.
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.
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.
(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 CCR4-NOT to control mRNA decay and 2 mitotic progression, Nature Structural & Molecular Biology, juin 2016