Objective
Only ~1.5% of the human genome encodes proteins; the remaining 98.5%, once dismissed as “junk”, harbors the regulatory blueprint of life. Non-coding DNA controls when and where genes switch on by guiding transcription factor (TF) binding and nucleosome organization, shaping nuclear architecture. Yet how billions of weak, dispersed interactions achieve the high level of specificity required for gene regulation remains a central mystery. Isolated TF binding is far too weak: targeting a single genomic site in the human genome would require >20 kBT of discrimination, while typical TFs reach at most ~10 kBT. This order‑of‑magnitude lack of specificity implies that collective processes underpin mesoscale nuclear structure.
Our work shows that these collective processes are sequence‑guided: TFs can undergo sequence‑dependent prewetting transitions to form TF condensates at specific locations. DNA thus encodes a rugged energy landscape that programs where droplets, loops, and topologically associating domains (TADs) emerge. In collective processes many weak interactions can outcompete a few strong ones, but current approaches fail to capture the vast sequence space of weak binding. We will develop Ising-like models of TF-DNA binding with sub-kBT precision for any sequence, calibrated by competitive binding assays and validated using optical tweezers coupled with MINSTED nanoscopy for near base pair resolution imaging of TFs on stretched DNA. These models will underpin a theory of structure formation via sequence-guided condensation and wetting, tested through optical tweezer-based measurements of prewetting and co-condensation. We will apply this framework to investigate the physical basis of promoter-enhancer communication and TAD-scale genome folding, and evaluate its impact on gene expression levels in cells. This project will establish a physical foundation for sequence-guided genome organization at the mesoscale and its future exploration in development and disease.
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 biochemistry biomolecules proteins
- social sciences sociology social issues social inequalities
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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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HORIZON.1.1 - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
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.
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.
Funding Scheme
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.
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.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2025-ADG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
80539 MUNCHEN
Germany
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.