I first learned about gene regulatory elements as a medical student in the early 2000s. Around the same time, the Human Genome Project provided the map of the human DNA sequence. This map, together with the broad implementation of next-generation sequencing technologies, enabled the large-scale exploration of the non-coding genome that has continuously fascinated me throughout the past 20 years. Today, mammalian gene activation is known to be tightly controlled by distant regulatory elements known as enhancers — first observed in the 1980s in the haematological system (more specifically, at the immunoglobulin heavy chain and β-globin loci). The role of enhancers in regulating gene expression has grown into a major field of study, but most findings are based on observations in cell lines and homogeneous, sorted cell populations that represent distinct developmental, differentiation or disease stages. Such studies probably miss enhancers with more transient dynamics during, for example, rapid transitions in cell stage.

A recent paper in Molecular Cell by Vermunt et al. reported a new phenomenon of transient enhancers. They observed that gene loci, at the moment of being silenced, can simultaneously activate enhancers in a highly transient manner. The authors call these enhancers ‘delay elements’ because their short-lived activation (approximately 24 hours) slows down the rapid silencing of gene loci. Several questions emerge from the findings by Vermunt et al. First, the biological relevance of the invoked silencing delay remains unknown. As the authors speculate, the delay may provide cells the additional time needed for upregulation of essential genes and thus prevent apoptosis. However, the in vivo consequences of losing delay elements have not yet been characterized. Second, it is unclear whether transient enhancer dynamics could also represent a mechanism for fine-tuning gene expression levels during gene activation. The authors do observe a significant enrichment of transient enhancers close to upregulated genes, however this association is not investigated further in the study. Third, it remains unknown whether there are many more transient enhancers yet to be discovered, but they potentially represent a large and exciting field to explore.