New genes, old job: the cell cycle evolves

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Scientists at EPFL have discovered that recently evolved genes play a key role in how our cells divide, revealing that even the most fundamental processes of life continue to evolve.

Image by OpenClipart-Vectors from Pixabay

Every day, our bodies perform around 330 billion cell divisions to keep us alive and functioning. These divisions rely on the cell cycle, which has been in place since the earliest bacteria. The principle is the same: double the cell’s content, then split into two “daughter” cells.

However, in more complex organisms, the cell cycle has become increasingly sophisticated. This raises a question: What role do recently evolved genes play in regulating this fundamental process?

Two scientists with the group of Didier Trono at EPFL, Romain Forey and Cyril Pulver, set out to answer this question. Combining cell cycle biology with genomics, they investigated how gene activity changes across cell division. Working with their colleague, Alex Lederer, they created a detailed atlas of human cell cycle gene activity, which is now available to researchers and the public. The study itself is published in Cell Genomics.

The project was distinctively interdisciplinary, which is characteristic of research at EPFL. “Romain oversaw all of the wet lab experiments and brought in his cell cycle expertise, whilst I took care of the genomics analyses,” says Cyril Pulver.

He adds: “However, we did not strictly adhere to those disciplinary boundaries, as key hypotheses, mathematical modelling and wet lab experiments were discussed and decided upon jointly. We are also indebted to Alex Lederer from the lab of Gioele La Manno, who performed a key analysis regarding the CRISPRi data, essentially positioning 1.9 million cells within the cell cycle according to their transcriptomes.”

Starting with the atlas, the researchers focused on a special group of genes: those that produce transcription factors—proteins that control which genes are turned on or off. They found that some of these transcription factors, which help guide cells through the cell cycle and ensure everything happens at the right time, have emerged surprisingly recently.

Specifically, the study revealed that several recently evolved transcription factors regulate genes that are active during specific phases of the cell cycle. When some of these factors were knocked down, the cells got stuck at specific stages or lost their usual timing compared to the rest of the cell population, disrupting the orderly flow of division.

One standout was ZNF519, a gene found only in primates. Disabling it caused the cells to struggle with copying their DNA correctly — a critical step before division — and as a result, their growth slowed down. The team confirmed that ZNF519 directly binds to the DNA of key cell cycle genes and acts as a repressor.

Another protein, ZNF274, found in mammals but absent in older reptiles, fish etc, was found to have an additional impact: it regulates the moment at which specific chunks of the genome are duplicated prior to mitosis, a process linked to epigenome maintenance, 3D organization and nucleus organization.

“We contribute a comprehensive resource regarding human cell cycle gene expression and perturbations, which we hope will be of use to our colleagues worldwide,” says Pulver.

The discovery shows that processes as ancient as cell division integrate new genetic players, some of which are specific to humans or our close relatives. This has implications for understanding diseases like cancer, where the cell cycle becomes dysregulated. It might also help explain why certain cancers or developmental disorders are more prevalent or behave differently in humans than other mammals.

The paper Evolutionarily recent transcription factors partake in human cell cycle regulation. was published in Cell Genomics. Authors: Cyril Pulver, Romain Forey, Alex R. Lederer, Martina Begnis, Olga Rosspopoff, Joana Carlevaro-Fita, Filipe Martins, Evarist Planet, Julien Duc, Charlène Raclot, Sandra Offner, Alexandre Coudray, Arianna Dorschel, Didier Trono.