Project description
Decoding how regulatory DNA shapes primate brain evolution
The molecular mechanisms driving species-specific differences, such as the human brain’s expansion, remain largely mysterious. With the support of the Marie Skłodowska-Curie Actions programme, the EvoNeuHance project aims to decode how changes in two key regulatory systems in neurons have evolved within and across species and how they modulate gene regulation. Enhancers – short, non-coding regions of DNA on the same chromosome as the target gene (cis-regulation) – turn expression on and off. Transcription factors – diffusible proteins (trans-regulators) that bind to enhancers – modulate enhancers’ activity. By combining functional genomics, synthetic biology and computational modelling to study four primate species, EvoNeuHance intends to generate the first cross-species atlas of enhancer activity during early brain development.
Objective
The human brain’s expansion is a hallmark of evolution, yet the molecular mechanisms underlying species-specific traits remain poorly understood. Regulatory DNA elements like enhancers are key drivers of neuronal gene expression, but how multiple sequence differences accumulated across species shape enhancer activity remains largely unknown. EvoNeuHance (EVOlutionary NEUronal enHANCEr grammar) aims to decode the cis-regulatory logic of enhancer evolution (sequence changes in DNA) and its modulation by the trans environment (availability of TFs and cofactors) during primate neurogenesis. Using massively parallel reporter assays in two relevant cell types across four primate species, I will generate the first cross-species atlas of enhancer activity during early brain development.
First, I will quantify the activity of 40,000 orthologous enhancers across primates and train predictive models linking sequence divergence with activity. Next, I will reconstruct enhancer evolution using synthetic variant libraries, including stepwise “species-morphed” gradients to identify sequence features driving cell- and species-specific activity. Finally, I will perturb candidate trans-acting factors with CRISPRi to test their influence on the activity of synthetic enhancer variants and apply genome engineering to revert endogenous enhancers to ancestral or synthetic states, assessing how cis- and trans-changes reshape regulatory outcomes and 3D chromatin architecture.
This interdisciplinary approach delivers the most comprehensive dissection of cis-trans enhancer logic across primates to date, combining functional genomics, synthetic biology, and computational modeling. Results will reveal how sequence divergence (cis) and cellular context (trans) jointly shape enhancer activity, uncovering principles of primate brain evolution and providing a blueprint for rational design of synthetic enhancers with translational potential in regenerative medicine and gene therapy.
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 zoology mammalogy primatology
- natural sciences biological sciences genetics DNA
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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.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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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.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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(opens in new window) HORIZON-MSCA-2025-PF
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85764 Neuherberg
Germany
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