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Development of novel single cell multi-omics methods to uncover regulators of cell type specific epigenetic states.

Project description

Identifying key factors of epigenetic mechanisms

Cells within an organism contain the same genetic information, yet they use it differently depending on their context. Epigenetic mechanisms, particularly post-translational histone modifications (PTHMs), play a role in regulating transcription factor-DNA interactions, and these modifications change during cell differentiation. While the proteins responsible for modifying PTHMs are known, how they are recruited to specific genomic sites remains unclear. The ERC-funded scEpiTarget project will develop advanced single cell methods to identify the key factors that influence cell type-specific PTHM deposition. The project will explore how PTHMs can be retargeted and evaluate their effects on cell fate decisions using cutting-edge cell differentiation systems. A novel technique will be used to measure histone modifications and total RNA in individual cells, integrating genetic screening and chromatin biology insights for a comprehensive understanding of the process.

Objective

Although all cells of an organism share the same genetic information, they selectively access this information in a cell type- and context-dependent manner. Epigenetic mechanisms, such as post-translational histone modifications (PTHMs) have been identified as central regulators of Transcription Factor-DNA interactions. During cell differentiation, the distribution of PTHMs is modulated to enable the new cell state. Most of the protein complexes that position (writer) and remove (eraser) PTHMs have been identified, but we still do not understand how these proteins are recruited to the genome and thereby dictate the specific genomic distribution of PTHMs. Previous studies were unable to identify these targeting factors as they only interact with a fraction of writer complexes at a time and likely form transient interactions. Thus, new experimental approaches are needed to identify these proteins that are directing localised epigenetic changes.
In scEpiTarget I will develop novel single-cell methods to identify the key factors that determine cell-type specific PTHM deposition. I will use the identified regulators to re-target PTHMs and evaluate their impact on cell fate decisions in state-of-the-art cell differentiation systems.
Recently, I made a technological breakthrough by developing a method that allows the simultaneous measurement of histone modifications and total RNA in single cells. Together with my background in genetic screening and chromatin biology, this will enable me to reach scEpiTargets objectives. The proposed techniques are transferable to study any protein:DNA interaction, making them highly valuable for the research community.
Epigenetic pathways are essential for multi-cellular life from the beginning of embryonic development, until their mis-regulation during ageing. The identification of factors regulating PTHM distribution will lead to a better understanding of their function and how they can be therapeutically influenced during pathogenes

Fields of science (EuroSciVoc)

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Host institution

AARHUS UNIVERSITET
Net EU contribution
€ 1 810 745,00
Address
NORDRE RINGGADE 1
8000 Aarhus C
Denmark

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Region
Danmark Midtjylland Østjylland
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 1 810 745,00

Beneficiaries (2)

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