Researchers from the Universitat Autònoma de Barcelona (UAB) have now published a pioneering analysis that reveals new functions of the RAD21L protein—a germline-specific cohesin—crucial for male fertility. The study, carried out in mice and in collaboration with the Spanish National Research Council (CSIC), the University of Salamanca, and the National Centre for Genomic Analysis (CNAG) of Barcelona, is published in the journal Science Advances.
Cohesins are ring-shaped protein complexes that surround the DNA and play an essential role in cell division, preventing the loss of genetic information. Among them is the RAD21L protein, which is expressed exclusively in germ cells (ovaries and testes) and is essential for the pairing of homologous chromosomes during genetic recombination. In animal models with deficiencies of this protein, researchers had observed defects in chromosome pairing and accumulation of unrepaired breaks in DNA, which produced male infertility.
The published study now demonstrates that RAD21L also regulates the three-dimensional organisation of the genome and gene expression in sperm precursor cells. The absence of this protein causes a profound reorganisation of the chromatin architecture and a general deregulation of gene activity, which interferes with the process of spermatogenesis and leads to infertility.
"This discovery adds a new dimension to our understanding of how genome structure influences fertility, genetic diversity and evolution", explains Dr Aurora Ruiz-Herrera, professor at the Department of Cell Biology, Physiology and Immunology at the UAB, researcher at the Institute of Biotechnology and Biomedicine (IBB-UAB), and ICREA Acadèmia, who led the study.
The research was carried out using genetically modified mice that do not have the RAD21L protein. Using advanced genomic techniques, the team analysed the three-dimensional structure of the genome and gene expression levels in male germ cells. The comparison between healthy and infertile mice allowed them to demonstrate that the lack of RAD21L alters the distribution of DNA in the cell nucleus and deregulates genes that are key to sperm formation.
According to Dr Laia Marín Gual, first author of the study and researcher at the IBB-UAB, "What was most surprising was to observe how the absence of RAD21L not only affects the physical structure of the genome, but also profoundly alters the activity of genes involved in the formation of gametes. This allows us to better understand the genetic mechanisms that may be behind certain cases of male infertility".
Implications for human fertility
Although the study was conducted in mouse models, researchers highlight that the mechanisms discovered could also be relevant in humans. Spermatogenesis is a highly conserved process among mammals, and the deregulation of proteins such as RAD21L could be involved in cases of idiopathic male infertility—those without an apparent cause—which affect millions of men worldwide.
Infertility affects about 17.5% of the world's adult population, according to data from the World Health Organization (WHO), which is equivalent to one in six people. In addition, recent studies show a reduction in sperm concentration worldwide since 1973. These data point to the fact that male infertility is a growing public health problem, and that its genetic origin remains largely unknown.
This finding not only improves basic knowledge on reproductive biology but also opens new avenues for the genetic diagnosis of male infertility. It also raises questions about the evolutionary role of RAD21L in genome architecture and regulation in different species, including humans.
The research team plans to delve deeper into the molecular mechanisms by which RAD21L regulates genome organisation and expression. Moreover, studying its function in other species could offer new insights into the evolution of fertility and genetic control.
Original article:
Marín-Gual L, Vara C, Sainz-Urruela R, Cuartero Y, Álvarez-González L, Felipe-Medina N, Garcia F, Llano E, Marti-Renom MA, Pendás AM, Ruiz-Herrera A. Meiotic cohesin RAD21L shapes 3D genome structure and transcription in the male germline. Sci Adv 2025 Oct 3; 11( 40): eadv2283. doi: 10.1126/sciadv.adv2283
