Project description
How (re-)positioning of regulatory elements affects gene activity
In mammalian genomes, enhancers (Es) can be positioned nearby or far from the promoter (P) that they regulate. The EU-funded RE_LOCATE project aims to develop a technology to transplant selected DNA elements to hundreds of alternative positions, revealing how the ordering and spacing of Es and Ps contribute to gene regulation. The researchers will combine this technology with a high-throughput combinatorial reporter assay to study the role of Es selectivity in activation of the correct Ps. Also, the technology will be used to map the loop extrusion that shapes E and P interactions, and fine-map the repressive/activating chromatin landscape at high resolution. This work will reveal how the positioning of regulatory elements along the genome contributes to optimal gene regulation.
Objective
"In mammalian genomes, the enhancers (E) that control a promoter (P) are often scattered over tens to hundreds of kb, and frequently interdigitate with Es that control other nearby Ps. How such apparently haphazard linear arrangements can result in specific gene regulation is a major puzzle. Three main constraints are thought to be involved. First, biochemical compatibility of Es and Ps may ensure that not all Ps respond equally strongly to a given E. Second, chromatin loops may either facilitate or curb particular E-P interactions. Third, Es and Ps are controlled by the local landscape of chromatin modifications. Much is still to be learned about these constraints and their interplay. To unravel the logic of this linear arrangement of Ps and Es, it is necessary to systematically alter the positions of Es, Ps, and elements that control looping. So far, no efficient method has been available for this purpose. We propose to develop and apply RElocate, a scalable, broadly applicable technology to transplant selected DNA elements to hundreds of alternative positions within a ~2 Mb region, and track the functional consequences. We will employ RElocate in combination with a high-throughput combinatorial reporter assay to systematically study how biochemical compatibility may dictate how Es ""choose"" and activate the correct target P(s). Furthermore, we will adapt RElocate to precisely map how loop extrusion shapes E-P interactions, by insertion of hundreds of unidirectional road blocks throughout a locus. Finally, we will use the method to fine-map the repressive/activating chromatin landscape of selected regions at high resolution, and elucidate how Es and Ps may respond differently when inserted throughout this landscape. This work will reveal how the ordering and spacing of regulatory elements along the genome contributes to optimal gene regulation, and will yield a powerful perturbation tool with many applications in genome biology and human genetics."
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: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciences biological sciences genetics DNA
- natural sciences biological sciences genetics genomes
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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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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.
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Call for proposal
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(opens in new window) ERC-2021-ADG
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1066 CX Amsterdam
Netherlands
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