Project description
Timing of enhancer-promoter interactions in gene regulation
Gene regulation in vertebrate development relies on enhancer-promoter interactions. Changes here can cause developmental disorders and cancers. However, these interactions do not always lead to gene activation, so their effects on transcription may be unclear. Timing is essential for activation. The ERC-funded TimedEnhancer project will investigate how the timing of enhancer-promoter interactions affects transcription during embryonic stem cell differentiation. It will uncover the molecular mechanisms behind transcriptional activation and the relationship between past and present interactions, using a genomic approach to add a temporal dimension to single-cell methods. By combining advanced genomic, single-cell, and perturbation techniques, the project will reveal how genes respond to multiple enhancers and the impact of genome folding timing.
Objective
During vertebrate development, genes are regulated by distal regulatory elements, presumably via physical contacts between enhancers and transcription start sites. Alterations in enhancer sequences and/or their interactions with gene promoters can perturb gene expression, leading to developmental disorders and cancers, which argues for their pivotal role in transcription. Conversely, enhancer-promoter contacts can also be uncoupled from gene activation during developmental transitions and in single cells, where they are highly heterogeneous. Thus, the relationship between enhancer-promoter interactions and transcription is frequently indirect and the mechanisms that dictate when promoter-enhancer contacts can result in gene expression differences remain unknown. The core hypothesis of this proposal is that it is the timing of promoter-enhancer communication that instructs gene activation.
Aim1 will examine whether and how the precise timing of enhancer-promoter interactions contributes to transcription. My group will determine which molecular mechanisms during transcriptional activation are regulated by enhancers contacting their target genes at different time points during embryonic stem cell differentiation.
Aim2 will investigate how present and preceding enhancer-promoter contacts relate to transcriptional activity and transcription factor binding in single cells. My group will develop a genomic approach to trace the memory of preceding interactions at gene regulatory elements, thus adding a novel temporal dimension to current single-cell methods.
By longitudinally combining cutting-edge genomic, single-cell and activity perturbation assays, my group will uncover how genes integrate regulatory inputs from several enhancers and assess how the timing of genome folding mechanistically contributes to this process. This research plan will newly elucidate temporality as a powerful feature that shapes the regulatory potential of enhancers and promoters.
Fields of science (EuroSciVoc)
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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.
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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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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2023-STG
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69120 Heidelberg
Germany
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