Project description
Intermediates in nucleosome remodelling reveal the role of nucleosome position
DNA is ‘stored’ in the nucleus in a condensed form known as chromatin that, when extended, looks like beads on a string. The beads are nucleosomes – histone proteins around which the DNA is wound. The precise position of nucleosomes impacts regulation of transcription, replication and DNA repair. Chromatin remodelling – active reorganisation of nucleosomes – is modulated by DNA sequence in an unknown way. Given that remodelling involves sequential catalytic cycles and intermediates, the ERC-funded DONUTS project aims to study the nature and stability of these transient intermediates. To do so, they will leverage molecular simulations, in vivo experiments, and a novel high-throughput platform combining single-molecule measurements of complex dynamics with next-generation sequencing.
Objective
Eukaryotic genomes are packaged into chromatin, which restricts access to the DNA. Key genomic processes therefore involve the rearrangement of chromatin by ATP-dependent chromatin remodelling enzymes (remodellers), which actively place and reorganise nucleosomes. The precise positioning of nucleosomes plays a crucial role in regulating transcription, replication, and DNA repair. DNA sequence impacts this nucleosome architecture by affecting the activity of remodellers. However, what mechanisms underlie this critical sequence dependence in remodelling remains unknown. Here, we propose to address this longstanding question based on the following rationale: the nucleosome represents a highly constrained substrate with many histone-DNA interactions. Remodeller action therefore involves multiple sequential catalytic cycles and a series of transient structural intermediates of the nucleosome. We hypothesise that the nature and stability of these intermediates determine the effects of DNA sequence on remodelling. Probing this hypothesis requires the direct observation of transient remodelling intermediates as a function of sequence at the genome scale, which cannot be achieved with currently existing methods. We aim to address this major challenge by developing a novel high-throughput platform that combines, for the first time, single-molecule measurements of complex dynamics with next-generation sequencing. This platform will enable the comprehensive profiling of sequence-dependent processes at the single-molecule level. We will leverage the platform in combination with molecular simulations and in vivo experiments to gain groundbreaking insights into the mechanisms of sequence-dependent remodelling and its role in the establishment of chromatin architecture. Ultimately, we expect to decipher how the dynamic landscape of nucleosome intermediates - encoded in the sequence wrapped around the histone core - impacts nucleosome function in vivo.
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.
- natural sciences biological sciences genetics DNA
- natural sciences biological sciences genetics genomes
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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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)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2022-ADG
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751 05 Uppsala
Sweden
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