Genes follow a random switching principle, yet remain precise on average

Inside the cell nucleus, genes must be turned on and off with precision to regulate biological processes. The first models of gene regulation were developed in the 1960s, yet modern science continues to uncover new layers of control. A new study involving researchers from the Institute of Science and Technology Austria (ISTA), the Institut Pasteur and Princeton University, published in PNAS, now suggests that genes obey an optimal switching principle-random at any given moment, yet precise on average.

Consider this simple analogy: Imagine an air conditioner with two modes, "on" and "off." Outside, it's 40 °C. When it's off, hot air fills the room; when on, it blasts cool air at 15 °C.

How can it be regulated to keep the room at a comfortable 25 °C?

Engineers have a solution called pulse‑width modulation: the system rapidly alternates between fully on and fully off, and what matters is how long it stays in each state-the average produces the desired temperature.

Cells face a similar challenge when regulating genes. A new theoretical framework developed by Professor Gašper Tkačik and Postdoc Alexis Bénichou at ISTA, together with Benjamin Zoller and Thomas Gregor (Institut Pasteur and Princeton University), explains how this might work. Zoller and Gregor's precise experimental data were incorporated into this theoretical publication.

Random-yet by design

There are many models that try to explain how cells precisely switch genes on and off. One well‑known concept, the telegraph model, assumes that genes activate in short bursts. Genes therefore flicker randomly between on and off, yet still generate highly precise gene‑expression patterns-for example, in the fruit fly."

Professor Gašper Tkačik, ISTA

What remained unclear was why cells would control gene expression using such a seemingly wasteful mechanism. If a gene should be active 80 % of the time, why not keep it steadily at that level instead of fluctuating between zero and 100 %? And if flickering is the chosen strategy, what governs the timing of these switches?

While air conditioners rely on engineered switches that can be toggled at any desired time with precision, cells lack such components. They cannot dictate the exact timing of each on or off change but can only modulate the probability of switching.

The new results indicate that gene flickering follows an organizing principle-one defined by a constant characteristic timescale.

"In physics, we call this the correlation time, 'Tc,'" Tkačik explains. "It remains constant no matter the desired expression level, enabling very precise expression control. This discovery was a big surprise because it is inconsistent with previously published models."

In short: it is random at any instant, yet precise on average.

Precision demands energy

Classical models often describe gene expression as a largely passive, equilibrium process: transcription factors randomly bind and unbind DNA, occasionally activating or silencing genes. This passive control consumes no energy.

However, the constant correlation time observed in the fruit fly cannot easily be explained by such equilibrium models. In eukaryotic cells, regulation appears to involve more complex, energy‑driven processes. The new study introduces a theoretical approach suggesting that gene switching operates out of thermodynamic equilibrium-it is powered actively and costs energy.

The next step, researchers say, is to test this prediction experimentally.

According to Tkačik, further work will aim to develop a fully mechanistic, physics‑based model-a set of equations calibrated by experimental data-to describe whether stochastic on‑off dynamics inside individual nuclei are caused by gene regulation actually being situated on the DNA polymer. It will also be evaluated how such dynamics can give rise to the highly precise gene‑expression patterns observed at the scale of an entire organism.