Un des tout premiers centres de recherche européens en biomédecine, l'IGBMC se consacre à l'étude du génome des eucaryotes supérieurs et au contrôle de l'expression génétique ainsi qu'à l'analyse de la fonction des gènes et protéines. Ces connaissances sont appliquées à l'étude des pathologies humaines comme le cancer et les maladies génétiques.

Tfiih Is A New Master Regulator Of Gcn5 Controlling Histone Ptms Upon Transcription

Reference : PhD Frédéric Coin

The transcription of protein-coding genes depends on RNA polymerase II (Pol II) associated with general transcription factors (GTFs) including TFIIH to form the pre-initiation complex (PIC) at promoters.

TFIIH can be resolved into two sub-complexes that are bridged by the XPD helicase subunit: the core (composed of the XPB and the subunits p62, p52, p44, p34, and TTDA) and the CAK (composed of MAT1, cyclin H, and the CDK7 kinase). The function of TFIIH in class II gene transcription initiation is dual involving XPB to open the DNA around the transcription start site (TSS) while the CDK7 kinase phosphorylates the C-terminal domain (CTD) of the largest Pol II subunit on the serine 5. Understanding the roles played by TFIIH is of prime importance since mutations on XPB, XPD or TTDA subunits give rise to the human autosomal recessive disorders xeroderma pigmentosum (XP), XP associated with Cockayne syndrome (XP/CS), and trichothiodystrophy (TTD).

Accumulating evidence suggests that the clinical features of these three disorders involve some transcription deficiencies. Based on the study of these defaults, our data have strongly suggested that TFIIH would possess additional roles beyond its implications within the PIC rending the transcriptional etiology of the related disorders still elusive. 

Indeed, by studying XP/CS patients derived-cells bearing the XPB F99S mutation, we have demonstrated that the transcriptional disruption is associated with deregulation of histone post-translational modifications (PTMs) deposited around promoters involving an interaction between TFIIH and the Histone Acetyl-Transferase (HAT) General Control of nutrition 5/ K acetyl-transferase 2A (GCN5/KAT2A). This enzyme is present in two functionally distinct coactivator complexes, SAGA (Spt Ada Gcn5 Acetyltransferase) and ATAC (Ada Two A Containing) that control several histone PTMs upon transcription at promoters. We hypothesize that mutations on TFIIH deregulate GCN5 leading to a lower expression of the target genes. However, the mechanisms behind our observations and its impact at the genomic scale are unknown.

The goal of this project is to (i) investigate the physical and functional interaction between TFIIH and GCN5 in SAGA/ATAC, (ii) identify the genes concerned and (iii) determine the importance of such mechanism for chromatin remodelling upon transcription in normal and pathological contexts, including cancer cells. The identification of genes and the pathways regulated by TFIIH would help to determine relevant markers for an early and specific diagnosis and would be useful to anticipate/predict the different symptoms.

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Date limite de candidature : 1 novembre 2018