Project description
Mechanistic insight into transcription factor target localisation
Gene transcription into messenger RNA requires the concerted action of transcription factors (TFs), proteins with DNA-binding domains that can bind to specific DNA sequences. Given the size and complexity of the genome and the small binding motif of TFs, it is puzzling how they find the correct sites. The working hypothesis of the EU-funded bInDR project is that specific regions within TFs known as long intrinsically disordered regions (IDRs) play a key role in TF specificity. Researchers will investigate the IDR-based molecular mechanism and generate a model of how TFs recognise their in vivo targets with great efficiency and specificity.
Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-ADG - Advanced Grant
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Call for proposal
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(opens in new window) ERC-2020-ADG
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7610001 Rehovot
Israel
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