Wednesday, October 15, 2025

Discovery of how a protein regulates DNA and affects male fertility

The study, conducted in mice, shows that a lack of RAD21L disrupts the structure of the genome and alters the activity of genes involved in the formation of sperm precursor cells.

Universitat Autonoma de Barcelona

Discovery of how a protein regulates DNA and affects male fertility — image:
RAD21L protein structure modelled with the AlphaFold artificial intelligence system.
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Credit: IBB-UAB

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.

Journal

Science Advances

DOI

10.1126/sciadv.adv2283

Method of Research

Experimental study

Subject of Research

Human tissue samples

Article Title

Meiotic cohesin RAD21L shapes 3D genome structure and transcription in the male germline

Historic photo of first successful embryo transfer in rhinos wins at Wildlife Photographer of the Year 2025 competition

Spanish photographer Jon A Juárez honoured at the Natural History Museum, London

Grant and Award Announcement

Leibniz Institute for Zoo and Wildlife Research (IZW)

image:
Winning photo in the "photojournalism" category at the "Wildlife Photographer of the Year 2025": Examination of a southern white rhino foetus as part of the science and conservation project "BioRescue", led by the Leibniz Institute for Zoo and Wildlife Research
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Credit: Jon A Juarez

Spanish freelance photographer and filmmaker Jon A Juárez, affiliated with the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW) in Berlin, has been awarded one of the world’s most prestigious distinctions in nature photography: the “Wildlife Photographer of the Year 2025 Award” (WPY) in the Category “photojournalism” at the Natural History Museum, London. His winning photo documents the world’s first successfully embryo transfer in southern white rhinos (Ceratotherium simum simum) — a scientific milestone offering renewed hope for saving its critically endangered northern relative (Ceratotherium simum cottoni).

The photographic assignment in Kenya, which covered the documentation of the worldwide first rhino foetus produced by in vitro fertilization and successful embryo transfer, was coordinated by the German Conservation and Research Fund e.V. (CRF) — a non-profit organisation supporting, amongst other things, visual documentation that bridges science, ethics, and wildlife conservation.

The bittersweet winning image: where science meets aesthetics

Jon A Juárez’s award-winning photograph was taken during a BioRescue pregnancy evaluation and shows an early-stage rhino foetus. The image captures the fragile intersection between biotechnology and life itself. “This photograph is more than scientific documentation — it’s a symbol of humanity’s capacity to take responsibility for species on the brink,” says Prof Dr Thomas B. Hildebrandt, BioRescue consortium leader from Leibniz-IZW.

“I wanted to tell the story of this foetus in a single image — one that would portray it with respect, while revealing its fragile, translucent skin that would soon fade away,” says award-winner Jon A Juárez.

Saving the northern white rhino from extinction

The BioRescue consortium has already produced 38 northern white rhino embryos. Before these can be transferred to surrogate mothers, it first had to be proven that embryo transfer could be successful in this species. The southern white rhino embryo was produced in vitro from collected egg cells and sperm and transferred into a southern white rhino surrogate mother at the Ol Pejeta Conservancy in Kenya on September 24, 2023. The BioRescue team confirmed a pregnancy of 70 days with a well-developed 6.4 cm long male embryo. The successful embryo transfer and pregnancy are a proof of concept and allow to safely move to the transfer of northern white rhino embryos – a cornerstone in the mission to save the northern white rhino from extinction.

Sadly, the pregnancy ended tragically when both the surrogate female rhino, Curra, and the vasectomised teaser bull, Ouwan, died in late November 2023 at the Ol Pejeta Conservancy. Exceptionally heavy rains had flooded the enclosure, releasing dormant Clostridium spores into the environment. Both animals succumbed to acute systemic infection and toxin-related poisoning caused by the bacteria. Tissue samples from the foetus were later analysed at the Max Delbrück Center and the Leibniz-IZW in Berlin, confirming the pregnancy’s scientific origin.

The Leibniz-IZW is a leading partner in the international BioRescue consortium, whose mission is to prevent the extinction of the northern white rhinoceros through advanced assisted-reproduction technologies and stem cell associated techniques and – after profound ethical assessment – eventually gene editing. BioRescue is primarily funded by the German Federal Ministry of Research, Technology and Space (BMFTR), formerly known as the BMBF. A proposal to secure the continued support of the BMFTR was submitted in the summer of 2025.

The BioRescue Consortium includes the following international partners:

Leibniz-IZW, Safari Park Dvůr Králové (Czech Republic), AVANTEA Laboratory of Reproductive Technologies (Italy), University of Osaka (Japan), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (Germany), University of Padua (Italy), Ol Pejeta Conservancy (Kenya), Wildlife Research & Training Institute (Kenya), and Kenya Wildlife Service (KWS)

About the “Wildlife Photographer of the Year” competition

The Wildlife Photographer of the Year (WPY) is an annual international competition run by the Natural History Museum, London, and is widely regarded as the world’s leading award for wildlife photography. The WPY competition, founded in 1965 (with some records tracing its first edition to 1964 under Animals Magazine, later BBC Wildlife), began modestly with just three categories — Mammals, Birds, and Other Animals. Over six decades, it has grown into a global institution featuring more than 20 categories. Today, it attracts tens of thousands of entries annually — 38,575 in 2022, 59,228 in 2024, and a record 60,636 in 2025 — from over 100 countries. Photographers may submit up to 25 images per year, which are judged anonymously by experts in photography, science, and conservation for originality, narrative strength, technical excellence, and ethical integrity. The winning and commended images are showcased in a major Natural History Museum exhibition that tours worldwide, inspiring millions of visitors each year.

Photographer Jon A Juarez on assignment for Leibniz-IZW

Credit

Jan Zwilling

Photographer Jon A Juarez documenting the northern white rhinos at Ol Pejeta Conservancy

Credit

Elena Gyldenkerne

Photographer and filmmaker Jon A Juarez on assignment for Leibniz-IZW

Credit

Jan Zwilling

Epigenetic “scars”: Unveiling how childhood trauma affects our genes

Researchers identify molecular markers in children and adolescents, revealing how child maltreatment stress alters DNA, brain development, and mental health

University of Fukui

Genome-Wide DNA Methylation Associations Across Developmental Cohorts — image:
Manhattan plots for the meta-analysis (Left). The solid dark red line indicates genome-wide significance (P = 9.0 × 10⁻⁸), and the dashed gray line shows the suggestive significance threshold (P = 1.0 × 10⁻⁶). The four probes that reached q-value significance are highlighted in light green and labeled with their corresponding gene names. Forest plot for the four significant probes (Right). Error bars represent the SEM.
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Credit: Senior Asst. Professor Shota Nishitani and Professor Akemi Tomoda from University of Fukui, Japan

Child maltreatment, which includes abuse and neglect, is one of the most serious public health concerns worldwide. These adversities leave a lasting impact on the emotional well-being, memory, and social development of affected individuals. The problem, however, reaches far beyond its psychological impact, affecting the brain and biological processes through genetic changes, which have remained unclear until now.

A recent study led by Senior Asst. Professor Shota Nishitani and Professor Akemi Tomoda from the Research Center for Child Mental Development at University of Fukui, Japan, in collaboration with Professor Masataka Nagao from the Department of Forensic Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan, reveals that child maltreatment leaves measurable biological “scars” on children’s DNA, leading to long-term alterations in the brain. The findings of the study were published in Molecular Psychiatry on September 16, 2025.

Their research builds on earlier findings from Prof. Tomoda’s group, which had revealed that child maltreatment can alter DNA. Unlike previous studies that focused on specific candidate genes, this current work employed a broader genome-wide approach, revealing novel molecular markers and directly linking them to brain structure.

Briefly, the researchers conducted a detailed analysis of the epigenome (a set of chemical “switches” on our DNA that regulate gene activity) across three different groups to identify biological markers linked to childhood maltreatment as trauma. Participants included those in judicial autopsy cases, as well as toddlers and adolescents who had undergone protective interventions, with the adolescents also undergoing brain MRI scans.

“We identified four DNA methylation sites that were consistently associated with child maltreatment, namely ATE1, SERPINB9P1, CHST11, and FOXP1,” explains lead author, Senior Asst. Professor Nishitani.

DNA methylation sites are key players in genetic regulation, as they can regulate the gene expressions without changing the underlying DNA sequence. While the researchers identified four different sites, the site FOXP1 was particularly significant as it acts as a “master switch” for the genes involved in brain development. The researchers found that hypermethylation of FOXP1 was linked to changes in gray matter volume in the orbitofrontal cortex, cingulate gyrus, and occipital fusiform gyrus of the brain regions which are responsible for emotional regulation, memory retrieval, and social cognition. This highlights the biological link between early trauma, brain development, and later mental health outcomes.

“Childhood trauma is not only a painful psychological experience but also leaves lasting biological marks at the molecular and brain levels,” explains Prof. Tomoda. “By identifying these epigenetic markers, we hope to develop new tools that can enable the detection and support of at-risk children as early as possible.”

To use their discovery for predictive analysis, the researchers created a methylation risk score (MRS) using the four identified DNA methylation sites. The score could successfully distinguish individuals with and without a history of maltreatment using external data independent of their own, suggesting its potential as an objective screening tool for identifying childhood trauma.

The significance of this discovery extends to multiple fields, including healthcare, forensic medicine, and public health policies. In healthcare, these biomarkers could help improve early diagnosis and personalized trauma-informed treatment approaches. While in forensics, it could help support investigations and support child welfare. Furthermore, the screening tools may also drive preventive care, reducing the long-term societal impact of maltreatment.

With these implications, the study also reflects the mission of the Division of Developmental Support Research at the University of Fukui, which integrates neuroscience, clinical practice, and community-based approaches to promote resilience and well-being for children and families. The center is dedicated to advancing the science and practice of child development and mental health, and focuses on early detection, intervention, and prevention of developmental and mental health issues.

“Childhood should be a time of safety and growth,” emphasizes Prof. Tomoda. “Understanding how childhood trauma affects us biologically can lead to better strategies for prevention, treatment, and support, helping break the cycle of maltreatment.”

***

Reference
DOI: 10.1038/s41380-025-03236-1

About University of Fukui, Japan
The University of Fukui is a preeminent research institution with robust undergraduate and graduate schools focusing on education, medical and science, engineering, and global and community studies. The university conducts cutting-edge research and strives to nurture human resources capable of contributing to society on the local, national, and global level.
Website: https://www.u-fukui.ac.jp/eng/

About Senior Asst. Professor Shota Nishitani from University of Fukui, Japan (Fiscal year 2019–2023)
Shota Nishitani, (Ph.D.), served as an Assistant Professor (Fiscal year 2019–2021) and a Senior Assistant Professor (Fiscal year 2022–2023) at the Research Center for Child Mental Development, University of Fukui, Japan. Prior to this role, he gained four years of extensive experience in epigenome-wide association studies as a Visiting Assistant Professor at Emory University (Fiscal year 2015–2018). His research aims to unravel the neurobiological mechanisms underlying child maltreatment and trauma. He addresses these questions by integrating computational approaches, such as epigenetic and neuroimaging bioinformatics, with experimental molecular biology techniques. He is now continuing his career as a Research Scientist at the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine.

About Professor Akemi Tomoda from University of Fukui, Japan
Akemi Tomoda, (M.D, Ph.D.), is a Professor and Director of the Division of Developmental Support Research at the Research Center for Child Mental Development, University of Fukui, Japan. Her areas of research interest include child psychiatry, neuroimaging of brain structure and function, attachment disorders, ADHD, and the effects of child maltreatment. Over her 35-year-long research career, she has published more than 140 peer-reviewed articles, along with multiple chapters, letters, and commentaries. Currently, her research focuses on child psychiatry, particularly on identifying the neurobiological and epigenetic consequences of child maltreatment.

Funding information
The study was supported by:
1. Japan Agency for Medical Research and Development (AMED) (Grant JP20gk0110052)
2. Japan Society for the Promotion of Science (JSPS) KAKENHI Scientific Research (A) (Grant JP19H00617)
3. JSPS KAKENHI Scientific Research (C) (Grants JP20K02700, JP21K02352)
4. Strategic Budget to Realize University Missions, University of Fukui
5. Research Grants, University of Fukui (FY 2019 and 2020)
6. Life Science Innovation Center, University of Fukui – Grants for Translational Research and Creative & Innovative Research (LSI20305, LSI22202)
7. Grant for Life Cycle Medicine, Faculty of Medical Sciences, University of Fukui

Upper panel: Whole-brain gray matter volume (GMV) comparison using voxel-based morphometry. The three identified brain regions are R.OFrC (right orbitofrontal cortex), L.MPCG (left medial/posterior cingulate gyrus), and L.OFuG (left occipital fusiform gyrus). Color bars indicate t-statistics. Lower panel: Correlation plots for FOXP1 with each of the GMV measures in these regions.

Credit

Senior Asst. Professor Shota Nishitani and Professor Akemi Tomoda from University of Fukui, Japan