New publication

More than the sum of its parts

Precise regulation of gene expression is crucial for the development and homeostasis of multicellular organisms. However, regulatory sequences, such as enhancers, are often located at vast genomic distances from their target gene, and it is still a mystery how enhancers communicate with their target gene. The Buecker lab has recently demonstrated how enhancers differentially located in the genome can cooperate to drive gene expression. In their study published in Molecular Cell, the researchers used a novel synthetic platform to reveal how weak and strong enhancers work together to amplify gene expression.

Dec 02, 2024

Enhancers – short non-coding DNA sequences that regulate transcription – can act at varying distances from their target genes. In their new study, the Buecker lab has developed an innovative synthetic gene expression reporter that enables the precise quantification of enhancer activity at distances of 1.5, 25, and 75 kilobases (kb) from the target promoter. This novel approach also allowed the researchers to elucidate how enhancers can cooperate to drive transcription, as group leader Christa Buecker explains: “In previous work, we've shown that enhancers can cooperate to regulate genes, even if they lack individual activity. This new study goes further by creating this synthetic gene locus, allowing us to test individual and combined enhancers at various distances to understand their cooperative effects.”

The researchers revealed that an enhancer's ability to activate gene expression from a distance is determined by its intrinsic properties rather than just its baseline strength. While some enhancers lose their activating potential as the distance increases, others partially retain it, showcasing a still enigmatic behavior. Christa explains: “We found that enhancers lose activity when placed far from their target gene, around 75 kb away, with some becoming completely inactive. However, introducing a second enhancer closer to the target at 25 kb, resulted in a combined, significantly stronger activation of the promoter. This finding suggests that enhancers can overcome distance limitations in the genome by working together synergistically.”

The Buecker lab’s proof-of-concept study establishes a new tool for systematically testing the number of enhancers, as well as different combinations in gene expression. This platform not only provides insights into enhancer cooperation but also lays the groundwork for broader applications. As part of a recently FWF-funded project, the team aims to expand the system using recombination-mediated cassette exchange (RMCE). This next step will enable the team to delve deeper into the molecular rules and mechanisms that govern gene expression.

Read the paper

DOI: 10.1016/j.molcel.2024.11.008

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