In the realm of cellular biology, the process of cell division stands as one of the most essential and conserved mechanisms sustaining life. Every day, approximately 330 billion cell divisions occur within the human body, a staggering rate that underscores the foundational nature of the cell cycle. This process, inherited from the earliest forms of life such as bacteria, involves a highly coordinated sequence: a cell duplicates its contents and subsequently divides into two genetically identical daughter cells. However, as organisms evolved in complexity, so too did the regulation of the cell cycle, integrating more intricate layers of control. This raises an intriguing evolutionary question: how do recently emerged genes influence the regulation of this ancient yet vital system?
A pioneering study led by the team of Didier Trono at the École Polytechnique Fédérale de Lausanne (EPFL) seeks to unravel this question by delving into the interplay between evolutionary novelty and cell cycle regulation. The research, spearheaded by scientists Romain Forey and Cyril Pulver with significant contributions from Alex Lederer, combines cutting-edge cell cycle biology techniques with genomics to provide an unprecedented view of gene activity dynamics during cell division. Their collaboration culminated in the creation of a comprehensive atlas charting human cell cycle gene expression, a resource now accessible to researchers and the wider scientific community through the journal Cell Genomics.
Distinctly interdisciplinary, this project blended experimental cell biology with high-throughput sequencing and computational genomics. Forey orchestrated the experimental side, executing wet lab procedures to probe cell cycle progression and perturbations, while Pulver focused on genomic data analysis. Their collaborative synergy ensured that key hypotheses, mathematical modeling, and experimental validations were seamlessly integrated, facilitating a robust and nuanced exploration of transcriptional regulation throughout the cell cycle. Alex Lederer’s essential role involved the CRISPR interference (CRISPRi) analysis, which positioned nearly two million individual cells within the cell cycle continuum based on their gene expression profiles, offering unprecedented resolution.
Central to the study was an in-depth focus on transcription factors—proteins functioning as master regulators that dictate gene activation patterns. The researchers identified a remarkable subset of these transcription factors as being evolutionarily recent additions, some unique to primates and mammals, rather than ancient, conserved elements found across a broad range of species. This finding altered the longstanding conception that cell cycle regulation is governed exclusively by ancient, deeply conserved genes. Instead, it revealed that evolutionary newcomers intricately fine-tune core cellular processes.
Among these recent transcription factors, ZNF519 emerged as a particularly compelling subject due to its presence exclusively in primates. Functional experiments demonstrated that knocking down ZNF519 impaired the cell’s ability to accurately replicate DNA, a critical preparatory step before mitosis. This disruption induced a slowdown in cellular proliferation, revealing ZNF519’s pivotal role in maintaining replication fidelity. Further molecular assays elucidated that ZNF519 binds directly to key cell cycle gene promoters, functioning predominantly as a transcriptional repressor, thereby exerting precise control over gene expression timing and ensuring orderly cell cycle progression.
Another notable protein uncovered was ZNF274, a transcription factor with evolutionary origins in mammals but absent in earlier vertebrates like reptiles and fish. ZNF274 exerts influence over the temporal regulation of genomic replication, specifically dictating when segments of the genome are duplicated during the synthesis phase prior to mitosis. This timing is critical for preserving epigenetic markers, the three-dimensional organization of the genome within the nucleus, and overall nuclear architecture. Such regulation suggests that mammals have evolved sophisticated mechanisms to integrate 3D genome structuring with fundamental biochemical replication processes, optimizing genome stability and cellular function.
The implications of these discoveries ripple beyond basic biology, offering fresh perspectives on disease mechanisms, particularly cancer. Since malignancies often hinge on dysregulated cell division, understanding how recently evolved transcription factors contribute to cell cycle control can elucidate why certain cancers exhibit human-specific vulnerabilities or distinct progression patterns. Moreover, developmental disorders linked to cell cycle anomalies might also be better understood through the lens of this evolutionary integration.
Importantly, this research provides a comprehensive, publicly available atlas of human cell cycle gene expression and the effects of genetic perturbations. Such an extensive resource equips the scientific community with tools to probe the nuances of cell cycle regulation, facilitating further discovery and potential therapeutic innovation. The atlas itself combines data from genome-wide expression profiles, CRISPR screening, and transcriptomic positioning, enabling researchers to contextualize gene activity within the precise temporal framework of the cell cycle.
The discovery that relatively recent genes participate actively in regulating one of biology’s oldest processes challenges the dogmatic view that fundamental cellular mechanisms are exclusively governed by ancient genetic components. Instead, it illustrates the dynamic nature of evolution where new genetic elements can be co-opted into established networks, introducing layers of regulation that may confer selective advantages in complex organisms. This evolutionary plasticity underscores the sophistication of human biology and opens new avenues for studying species-specific cellular behaviors.
From a technical standpoint, the study combined sophisticated methodologies including CRISPRi-based functional genomics, single-cell RNA sequencing, and computational modeling. By integrating nearly two million individual cell transcriptomes and mapping their position in the cell cycle, the team was able to identify phase-specific gene expression with remarkable precision. This granular approach allowed the detection of subtle regulatory roles of transcription factors that might have been overlooked in bulk analyses, highlighting the power of single-cell technologies in dissecting cellular complexity.
The interdisciplinary nature of this work, bridging molecular biology, genetics, and computational modeling, exemplifies the new frontier of biomedical research. It showcases how combining diverse expertise and methodologies can yield insights unattainable through traditional siloed approaches. The collaboration within the EPFL research community, including input from Gioele La Manno’s laboratory, which specializes in single-cell data analysis, was pivotal to the project’s success.
Ultimately, this study not only advances fundamental understanding of cell cycle regulation by revealing the role of evolutionarily recent genes but also provides a platform for future investigations into how these regulators might contribute to human-specific disease phenotypes and developmental processes. It underscores the importance of evolutionary perspectives in contemporary biomedical research and paves the way for breakthroughs in personalized medicine and targeted therapies.
Subject of Research: Regulation of human cell cycle by evolutionarily recent transcription factors
Article Title: Evolutionarily recent transcription factors partake in human cell cycle regulation
News Publication Date: 23 June 2025
Web References: http://dx.doi.org/10.1016/j.xgen.2025.100923
References: Pulver C., Forey R., Lederer A.R., et al. (2025). Evolutionarily recent transcription factors partake in human cell cycle regulation. Cell Genomics. DOI: 10.1016/j.xgen.2025.100923
Image Credits: Pulver et al., 2025
Keywords: cell cycle, transcription factors, human evolution, CRISPRi, single-cell RNA sequencing, DNA replication, genome organization, cell division regulation, ZNF519, ZNF274, epigenetics, cell proliferation
