Description du projet
Aperçu mécanistique sur la localisation de cibles des facteurs de transcription
La transcription des gènes en ARN messager implique l’action concertée de facteurs de transcription (FT), des protéines dotées de domaines de liaison à l’ADN capables de se lier à des séquences d’ADN spécifiques. Étant donné la taille et la complexité du génome et la dimension réduite du motif de liaison des FT, il est étonnant qu’ils parviennent à trouver les sites exacts. Selon l’hypothèse de travail du projet bInDR, financé par l’UE, des régions spécifiques situées à l’intérieur des FT, appelées longues «régions intrinsèquement désordonnées» (RID ou IDR, en anglais), jouent un rôle clé dans la spécificité des FT. Les chercheurs étudieront le mécanisme moléculaire fondé sur les IDR et élaboreront un modèle sur la manière dont les FT reconnaissent leurs cibles in vivo de façon très efficace et spécifique.
Objectif
How transcription factors (TFs) bind rapidly at specific sites within large genomes remains a major mystery. Specificity is puzzling since TFs select a small fraction of their potential binding sites - short and highly abundant DNA motifs. Rapid detection of these selected sites is challenging due to the small motif size and the large number of non-specific sites within a genome. Despite extensive efforts, a unifying model accounting for these challenges, underlying the foundations of gene regulation, is still missing.
Our recent results revealed an unexpected role of long intrinsically disordered regions (IDRs) in determining the in-vivo binding specificity of TFs. Long IDRs are ubiquitous among eukaryotic TFs, but their potential role is largely unknown. By studying two budding yeast TFs, we found that in-vivo binding specificity depends on long (>500 residues) IDRs located outside the DNA binding domains (DBDs). Furthermore, IDRs direct TF binding to the selected set of promoters using multiple weak specificity determinants distributed throughout their entire sequence.
Our results suggest that TFs search for their binding sites through a two-tier process: Specificity determinants distributed within long IDRs direct TFs to broad promoter regions, allowing for subsequent localized search of the DBD for its short binding motif. We plan to establish this model by: (1) Defining the molecular basis of IDR-promoter recognition and its sequence recognition code, (2) Defining the dynamic profile of IDR-based DNA recognition, and (3) Elucidating the evolutionary implications of this novel recognition mode.
Through a combination of experiments, computation and theory, carried out by an interdisciplinary group of students, our study will establish a new paradigm that explains the efficiency and specificity of the search of TFs for their in-vivo binding targets, providing a new solution for a long-standing mystery.
Champ scientifique
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ERC-ADG - Advanced GrantInstitution d’accueil
7610001 Rehovot
Israël