How a multitasking protein keeps the body’s clock in sync

If your genes could set an alarm clock, EZH1 might be the one ringing the bell.

A new study has revealed how this underappreciated protein ensures the rhythmic expression of genes in skeletal muscle, aligning them with the body’s 24-hour internal cycles[reference]Liu, P. et al. PRC2-EZH1 contributes to circadian gene expression by orchestrating chromatin states and RNA polymerase II complex stability. The EMBO Journal 43, 23 (2024).| article.[/reference].

A KAUST-led research team showed that EZH1 plays a dual role in circadian regulation. It both stabilizes a critical protein called RNA Polymerase II — the molecular engine of gene transcription — and reshapes the structure of chromatin, the tightly packed form of DNA, to activate or silence genes on schedule.

Thanks to this surprising versatility, EZH1 functions like a maestro, ensuring that genes involved in metabolism, sleep and other essential processes rise and fall on cue. When the protein’s activity declines — as may occur with aging — genetic timing can falter, leading to metabolic imbalances and disease.

“EZH1-mediated rhythmicity could play a key role in maintaining the fidelity and adaptability of tissue-specific genetic programs,” says Peng Liu, who co-led the study with colleague Valerio Orlando.

The research team — which included imaging specialist Satoshi Habuchi and stem-cell biologist Mo Li — made these discoveries by studying skeletal muscle tissue from mice and conducting experiments on cultured mouse muscle cells. By tracking gene expression and protein activity over a 24-hour cycle, they found that EZH1 levels oscillate in tandem with other master circadian genes. This rhythmic pattern allows EZH1 to regulate thousands of other genes tied to the body’s internal clock.

One of EZH1’s key roles, the researchers discovered, is stabilizing RNA Polymerase II — the enzyme that converts DNA-encoded instructions into RNA intermediaries — in a process known as transcription, which drives protein production and cellular function. At the same time, EZH1 modifies chromatin by adding or removing chemical tags. These epigenetic adornments make genes more or less accessible for transcription.

The two functions of EZH1 work together to maintain a precise rhythm of gene expression, notes Orlando, an unexpected finding that, he says, “highlights the importance of continuing to explore the basic aspects of epigenetic mechanisms.”

The study also revealed the consequences of EZH1 malfunction. When the researchers disrupted EZH1 in cells, they found that the rhythmic expression of numerous genes fell out of sync.

This misalignment could lead to problems such as impaired muscle repair, disrupted metabolism and increased susceptibility to age-related diseases — conditions that might one day be treated by targeting EZH1 and its pathways with new medicines. Supporting this idea, the KAUST-led team demonstrated that restoring EZH1 function largely reinstated the disrupted rhythms.

Many questions remain, including how EZH1 functions outside muscle tissue. Genome-wide analyses showed that disrupting EZH1 dampened the rhythmic transcription of over 1,000 circadian-regulated genes. While some of these genes are tied to skeletal muscle function, many are involved in broader metabolic and cellular repair pathways.

As researchers continue to unravel the complexities of EZH1, the latest findings underscore a critical new insight: this understudied protein orchestrates genetic timekeeping with precision, ensuring our bodies run like clockwork.

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