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Dependence Of NUcleosome Transactions on Sequence
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...
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.
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Duración del proyecto: 63 meses
Fecha Inicio: 2023-07-14
Fecha Fin: 2028-10-31
Fecha Fin: 2028-10-31
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-07-14
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2022-ADG:
ERC ADVANCED GRANTS
Cerrada
hace 2 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
UPPSALA UNIVERSITET
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5