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Laboratory | Bioinformatic | Genomics | Epigenetics
Transcriptional Regulation of Genomes
In eukaryotes, transcription as a first step of gene expression is tightly regulated and many multiprotein complexes are implicated in this essential process. Mediator of transcription regulation is one of these complexes essential during the activation of RNA polymerase II. This coactivator is responsible for the recruitment of RNA polymerase II to promoters in response to transcription activators. Mediator is a large multi-protein complex (1.5MDa) composed of 25 - 30 subunits and conserved in all eukaryotes. As expected given its central role in transcription activation, mutations in its subunits are involved in pathologies like cancers. The crucial role of Mediator in transcription activation is now largely accepted. However, the complexity of this complex has precluded a detailed understanding of the mechanisms of its action that is one of the keys for understanding gene expression regulation. Previously, using the two-hybrid approach we proposed a model of the organization of the complex. Many interactions that we uncovered were confirmed by crystallographic studies.
The general transcription factor TFIIS, that plays an important role in transcription elongation, is a partner of Mediator and the SAGA coactivator, which also plays a role in activation. We have shown that Mediator and TFIIS cooperate in the activation of a subset of the yeast genome. The analysis of TFIIS distribution on the genome unexpectedly indicated its presence on RNA polymerase III-transcribed genes in addition to those that are transcribed by RNA polymerase II. We demonstrated that TFIIS plays an important role in RNA polymerase III transcription, stimulating the transcription of this class of genes. We further extended this work on the genome of mouse embryonic stem cells and found that TFIIS function in RNA polymerase III transcription is conserved in mammals. These findings have led to reconsider and to extend largely the role of TFIIS transcription factor in genome expression.
We are now interested in the role of Mediator in transcription activation and, in particular, in preinitiation complex formation. Using the yeast Saccharomyces cerevisiae as our main model and integrative biology approaches, we have established the role of Mediator in the recruitment of Pol II and a general transcription factor TFIIH, contributing to our understanding of Mediator function. Our study has led to the discovery of an essential role of Mediator in TFIIH general transcription factor recruitment and allows us to propose a new model in preinitiation complex formation during transcription activation.
Mediator is essential for transcription of all genes in yeast. Moreover, it interacts with RNA polymerase II. We identified one subunit in Mediator and one in RNA polymerase II that directly contact each other. We showed that this contact is required for transcription of all genes in yeast, dissecting an essential mechanism for the expression of genomes in eukaryotes.
Currently, we are investigating the role of the 10 essential subunits of Mediator in stimulating the assembly of preinitiation complexes genome-wide using genetic, biochemical and functional genomics approaches. We are trying to uncover the rules that determine the pathways of assembly of preinitiation complexes in vivo.
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