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Epigenetic editing to unravel the causal function of Marks of Active Chromatin: a quantitative and mechanistic dissection

Project description

Quantitative and mechanistic insights into causal functions of active chromatin marks

Chromatin modifications are vital for the transcriptional programmes that support development and cellular identity. However, the causal functions and mechanisms of chromatin marks in gene regulation are not well understood. With the support of the Marie Skłodowska-Curie Actions programme, the MAChro project aims to methodically examine the causal roles of key active chromatin marks at a mechanistic and quantitative level. Using a novel epigenome editing tool, it will directly link locus-specific active mark deposition to transcriptional responses. This tool will then be combined with unbiased genome-wide CRISPR screens to systematically reveal the molecular mechanisms that decode the function of active marks. Finally, it will analyse the quantitative effects of these marks on transcription using a tuneable epigenetic editing platform.

Objective

Chromatin modifications are essential for the transcriptional programmes underpinning development and cellular identity. However, an understanding of the causal function(s) of chromatin marks in gene regulation has lagged behind. Particularly, whether chromatin modifications linked with active transcription (active marks) have a causal function remains intensely debated, while the underlying mechanisms are poorly understood. This is due to technical limitations in the ability to precisely perturb chromatin marks in a locus-targeted manner. In this project, I will leverage cutting-edge (epi)genomic tools to systematically dissect the causal roles of key active chromatin marks—H3K4me3, H3/H4ac, and H3K79me2—, at a mechanistic and quantitative level. To directly link locus-specific active mark deposition to transcriptional responses, I will employ a novel epigenome editing technology that allows precise and targeted deposition of chromatin marks. By combining this advanced tool with unbiased genome-wide CRISPR screens using the orthogonal enCas12a system, I will systematically uncover the molecular mechanisms that decode the function of active marks. Additionally, I will dissect the quantitative effects of these marks on transcription at the single-cell level using a tunable epigenetic editing platform. If successful, this proposal will provide unprecedented mechanistic insights into the role of active chromatin marks, paving the way to new therapeutic strategies that harness precise epigenetic control of gene expression.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2024-PF-01

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Coordinator

EUROPEAN MOLECULAR BIOLOGY LABORATORY
Net EU contribution

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.

€ 209 483,28
Address
Meyerhofstrasse 1
69117 Heidelberg
Germany

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Region
Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis
Activity type
Research Organisations
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Total cost

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