On and off: scientists describe mechanism to regulate gene transcription

The development of organisms depends on the correct regulation of gene expression, including the silencing of genes that should not be active. This repression is controlled by specialised transcription factors that recruit co-repressors to silence transcription, even in the presence of activating cues. Until now, scientists did not know whether co-repressors can broadly silence all enhancers or display distinct specificities. In the current issue of the journal Science, a team of researchers from the lab of Alexander Stark at the IMP show that most enhancers can be repressed by only a subset of co-repressors.

The “correct” expression of genes to build proteins is mediated by transcription, the formation of an RNA copy of the specific DNA-section that is a gene. This is arguably the most fundamental process of life, steered by the precise switching “on” and “off” of transcription – activation and repression.

Although the repression of transcription is so fundamentally important, our understanding of the interactions between well-known transcriptional corepressors and active enhancers is still patchy. A handful of examples suggest that not all repressors can silence all activators, but scientists are still in the dark about how common corepressor-enhancer specificities are, and which regulatory rules such specificities might govern.

In the journal Science, researchers from the lab of Alexander Stark now present the first categorisation of enhancers according to their sensitivity towards different co-repressors. Their findings explain how certain transcription factor motifs underlie these enhancer sensitivities, revealing a new level of specificity in transcriptional regulation between repressors and activators. The mechanism allows for a new way to modulate gene expression levels with extremely high specificity within a cell.

The scientists mapped the regulatory specificities between five prominent co-repressors and a genome-wide enhancer library in a cell culture line of the fruit fly Drosophilamelanogaster. To do this, they employed a technology to measure enhancer activities and strengths in the genome called STARR-seq, which was first developed in the Stark lab a decade ago and continues to be further modified and used. Looking at the enhancers, the scientists found widespread and distinct specificities towards different co-repressors, which allows the distinction between different enhancer types. These enhancer types further differed in the presence of activating transcription factor motifs.

“We are really excited about the specificities between co-repressors and transcription factors,” says Jelle Jacobs, postdoctoral researcher in the Stark lab and first-author of the study. “They don’t just suggest that repression occurs via distinct mechanisms, but also reveal a layer of ‘resistance’ against repression that wasn’t on the radar before.”

The discovery was made from an underappreciated direction: “In the past 30 years, a lot of attention was on the activation of genes,” says Alexander Stark. “Activation is of course important, but the other side of the medal – repression – must not be neglected. We now show an example for this: to deactivate genes and give a cell its specific identity, certain repressors need to be used.”

The uncovered layer of specificity between activating and repressing cues gives flexibility to a cell or organism to fine-tune gene expression. The discovery poses an opportunity for further research into how exactly the distinct mechanisms of gene activation and repression interact with each other.

Original Publication

Jelle Jacobs, Michaela Pagani, Christoph Wenzl, Alexander Stark (2023): “Widespread regulatory specificities between transcriptional corepressors and enhancers in Drosophila.” Science. DOI: science.org/doi/10.1126/science.adf6149