The hidden DNA organizer linking fertility and cancer

This research is led by Prof. Mitinori Saitou, Director/Principal Investigator at the Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University (also Professor at the Graduate School of Medicine), Dr. Masahiro Nagano (then Assistant Professor at the Graduate School of Medicine, currently Research Fellow at ASHBi and Postdoctoral Researcher at the Massachusetts Institute of Technology), and Dr. Bo Hu (then Ph.D. student, currently Research Fellow at ASHBi). The results of this study will be published online in Nature Structural & Molecular Biology at 10:00 am GMT (6:00 pm Japan Standard Time) on August 25, 2025.

Background

Our bodies contain many different types of cells, yet they all contain the same DNA. What makes each cell type unique is how this DNA is modified, packaged, folded, and organized. Think of DNA as a very long piece of string. Inside every nucleus, about two meters of this DNA string must be folded and stored in a space smaller than the width of a human hair. This folding is highly organized, with special boundaries called insulation that separate different regions of DNA and control which genes are turned on or off. Ring-shaped protein complexes called cohesins serve as the key players that create these boundaries. Cohesin complexes were previously thought to exist in two main forms: mitotic cohesins (contain STAG1 or STAG2 together with RAD21) and meiotic cohesins (contain STAG3 together with REC8 or RAD21L).

Germ cells are unique because they pass DNA to the next generation, and they undergo major changes in DNA folding during development. These cells undergo massive reorganization of their DNA packaging during development. Notably, SSCs have a unique way of organizing their DNA with unusually weak boundaries, but scientists do not yet understand how this happens.

Key findings

Because cohesin complexes contribute to DNA boundaries, and SSCs are mitotically dividing cells before entering meiosis, the research team decided to map where different cohesin proteins were located in SSCs cultured in vitro, and which proteins were present at each site. They found that RAD21, which normally partners with STAG1 or STAG2 in dividing cells, was instead partnering with STAG3. This protein was previously thought to function only during meiosis. Using immunoprecipitation-mass spectrometry (a technique that identifies which proteins stick together), they confirmed that RAD21 and STAG3 form a complex, revealing a new type of cohesin, which they referred to as STAG3-cohesin.

To find out what this new complex does, the researchers created two types of genetically modified SSCs in vitro: one set completely lacked STAG3, while the other contained only STAG3 (without STAG1 or STAG2). They discovered that STAG3-cohesin is responsible for the unusually weak DNA boundaries in SSCs. Most importantly, in mice missing STAG3, the SSCs could not progress from their stem-cell state to the next stage of sperm development in an efficient manner. This led to a fertility problem, showing that STAG3-cohesin does more than organize DNA and is critical for proper germ cell development.

As STAG3 functions in mitotically dividing cells, the team then investigated whether it might also function in other human cell types. By analyzing large datasets of all human cell types, they found that STAG3 is highly expressed in immune B cells and in B-cell lymphomas, a type of blood cancer. Interestingly, blocking STAG3 caused these lymphoma cells to grow much more slowly in laboratory studies, suggesting that STAG3 could be explored as a possible target for future cancer research.

Outlook

This study has revealed STAG3-cohesin as a new type of DNA-organizing protein complex that works very differently from previously known complexes. Because of its unique properties, further research on this complex is expected to advance our understanding of how gene activity is controlled through DNA organization. One of the most striking discoveries was that simply changing STAG3 levels could alter the proportion of stem cells in the testis. This suggests a novel mechanism that regulates the SSC state at the boundary between normal cell division and the start of meiosis.

Beyond germ cells, the discovery that blocking STAG3 slows the growth of B-cell cancers points to a possible role for STAG3 in future cancer research. Although more research is needed to uncover the precise mechanisms, these findings offer new insights that could advance stem cell biology, reproductive medicine, and cancer treatment.

Glossary

• Spermatogonial stem cells (SSCs): The stem cells in the testis that self-renew and also differentiate to give rise to sperm.
• Mitosis: The process by which a cell produces identical copies of itself, resulting in daughter cells with the same genetic information.
• Meiosis: A specialized form of division unique to germ cells, through which sperm or eggs are generated.
• Insulation: The "boundaries" within the 3D structure of DNA. They prevent enhancers (DNA elements that help turn genes on) from influencing genes across the boundary, effectively dividing the genome into separate functional regions.
• B cells: Immune cells that play a central role in antibody production within the immune system.
• Cohesin complex: A ring-shaped protein complex that holds chromatids together and helps organize DNA into loops essential for gene regulation and mitosis.