Temporal dependence of enhancer function

Introduction

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.

Enhancer-Promoter Interactions

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. 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.

Aim 1: Timing of Enhancer-Promoter Interactions

Aim 1 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.

Aim 2: Enhancer-Promoter Contacts in Single Cells

Aim 2 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.

Research Methodology

By longitudinally combining cutting-edge genomic, single-cell, and activity perturbation assays, my group will uncover how genes integrate regulatory inputs from several enhancers. We will assess how the timing of genome folding mechanistically contributes to this process.

Conclusion

This research plan will newly elucidate temporality as a powerful feature that shapes the regulatory potential of enhancers and promoters.