When a cell receives a signal (like a hormone), it needs to turn specific genes on quickly and precisely. But gene activation is not always immediate. Often, the molecular machinery responsible for making RNA begins its work and then pauses, waiting just downstream of the gene’s starting point. For years, scientists have known that this pause exists, but why cells hold their genes in this suspended state has remained unclear.
A recent study at NCBS takes a closer look at what happens during this pause by studying estrogen signalling. Turns out, this brief halt helps genes prepare for a stronger and more coordinated response when the signal finally arrives.
“We chose to study estrogen signalling because it allows us to learn about transcription factors in a system where genes need to be turned on quickly,” says Dr Rajat Mann, the lead author of the study
Rajat and team focused on estrogen receptor alpha, a protein that responds to the hormone estrogen. When estrogen enters a cell, this receptor binds to DNA to activate genes involved in growth and development. Using human breast cancer cells as a model, Rajat and team asked how estrogen receptor binding changes when RNA polymerase - the enzyme that makes RNA - is forced to remain in its paused state.
They found that pausing the polymerase led to a widespread increase in estrogen receptor binding across the genome. The receptor not only bound to more sites, but also stayed attached for longer periods. “This suggests that paused genes are already primed to recruit transcription factors,” says Rajat “The pause creates a favourable environment that allows these factors to bind more stably.”
One reason for this stability lies in short RNA molecules. Even when RNA polymerase is paused, it produces small fragments of RNA that remain close to the DNA. The research team discovered that these short RNAs physically interact with the estrogen receptor, helping it stay bound to chromatin. When these RNAs were removed, receptor binding dropped. When they accumulated, binding became stronger.
This interaction turned out to be essential. A version of the estrogen receptor that could not bind RNA failed to show increased binding at paused genes. “It’s the RNA that makes the difference,” says Dr Dimple Notani, the principal investigator of the study. “Without it, the receptor cannot take advantage of the paused state,” she added.
Pausing also changed the local chromatin environment. Genes with paused polymerase showed higher levels of a chemical mark associated with active transcription. These marks did not turn genes on immediately, but they made them more responsive. When the pause was released, these genes produced a much larger burst of RNA compared to genes that had not been primed.
“This study reveals how promoters utilise pausing to increase their transcription. The work also suggests that RNA is not a passive byproduct of transcription, but as a feedback, it plays structural and functional roles,” explains Dimple.
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