Cortisol resets cellular clocks by accelerating the conversion of <i>Per1</i> RNA into instructions for protein production

Cortisol resets cellular clocks by accelerating the conversion of Per1 RNA into instructions for protein production

On 13 August, a preprint reported how a hormonal signal tells cells the time of day. In human and mouse cells, the authors linked the resetting of internal clocks to a rapid increase in mature Per1 RNA and PER1 protein.

The cellular clock is a system of daily protein oscillations that allows a cell to align its internal time with the rhythm of the organism. Cortisol, a glucocorticoid hormone, carries this timing signal to peripheral tissues. A study published in 2000 showed that glucocorticoids can reset these clocks. The new preprint traces the molecular step that connects a brief hormonal pulse to a phase shift.

The authors first tested the role of the glucocorticoid receptor, a protein that binds the hormone and transmits its signal within the cell. A selective receptor activator shifted the phase. Two drugs that block the receptor abolished this effect, and deletion of the receptor gene prevented the cells from responding to the hormone. In cells lacking the receptor gene, an engineered receptor variant that remained permanently in the nucleus restored the response. These experiments allowed the authors to distinguish receptor activity from other possible hormone signaling pathways.

They then examined Per1, a gene involved in the molecular clock. Its mature RNA provides the instructions needed to produce PER1 protein. After the hormonal pulse, mature Per1 RNA increased far more than could be explained by the synthesis of new RNA. In human cells, PER1 levels began to rise within 12 minutes. In mouse lung explants, an inhibitor of new RNA elongation did not suppress the rapid Per1 response, whereas an inhibitor of protein synthesis abolished it.

“The rapid increase in Per1 RNA results from enhanced RNA processing rather than RNA synthesis,” the authors write.

The authors tested the connection to clock phase separately. In human cells, temporary depletion of PER1 weakened the response to a synthetic glucocorticoid. A brief increase in PER1 synthesis was sufficient on its own to shift the phase of the cellular clock.

About 20% of individual cells responded to the first hormonal pulse. In microfluidic culture, daily pulses strengthened the overall oscillation, especially after the second pulse. The authors attribute this effect to an increase in the proportion of cells converging on the same phase. In their cellular model, a recurring hormonal rhythm gradually brings an increasing proportion of cells into a shared phase.