Overlooked RNAs Act as Timing Switches for Genes in Embryos

Nobody knew whether these enhancer RNAs did anything meaningful during animal development or were merely biological noise. As a postdoctoral fellow at Princeton, and later in his own lab, Batut decided to test the question directly.

He developed real-time visualization techniques to watch endogenous noncoding RNAs and genes at work inside developing fruit fly embryos, which share many biological processes with humans. In plain terms: he built a live feed of gene activity in a growing embryo.

The first results showed that a large set of enhancer RNAs appeared at precise locations and precise times in the embryo — and seemed to coordinate the activation of HOX genes, a family of developmental regulators that pattern the body plan.

What did the experiments show?

The team then used genome editing to block one HOX gene's enhancer from producing its noncoding RNA. They expected the gene to switch off, or at least fade.

Instead, the opposite of a shutdown happened: the HOX gene turned on in the right place but at the wrong time, producing visible changes in the embryo's morphology.

"This showed us that these noncoding RNAs are not controlling whether the gene is switched on, but rather when it is switched on," Batut says.

Follow-up experiments revealed that activating these genes depends on a carefully coordinated "launch sequence," triggered by the enhancer RNA.

How do the RNAs work?

Enhancers can sit very far from the genes they regulate — sometimes thousands or millions of DNA bases away on a chromosome. DNA folding often bridges that distance, bringing enhancer and gene into physical contact.

"One aspect of how these noncoding RNAs work is that they seem to regulate the formation of these long-range DNA loops, which then controls the timing of gene expression," Batut explains.

At Columbia, his lab is now probing exactly how enhancer RNAs coordinate gene activity. "It's not just structural proximity between enhancers and genes; they are probably doing other interesting things as well, and those are questions we're trying to disentangle," he says.

What are the limitations and open questions?

The findings come from fruit flies, not humans, so any medical relevance remains preliminary. But similar enhancer RNAs occur widely in animals, including humans, and genetic dysregulation is already known to drive numerous human diseases. Noncoding RNA likely participates in many of those pathogenic processes.

"Their role in controlling timing is probably far more widespread than a couple of exotic genes," Batut says.

Because many mutations disrupt when and where genes are active, the work may point toward new therapeutic strategies — though that translation lies well ahead.

"That's why basic research is so wonderful; not only is it intellectually fascinating, but it also helps us understand how things break down and potentially how to fix them," Batut says.

Publication: Philippe J. Batut et al., Noncoding transcription controls the developmental dynamics of long-range gene regulation, Science (2026). DOI: 10.1126/science.aek5696.

In short: a once-ignored class of RNA tells developing genes not whether to fire, but when.