Health

The hidden DNA organizer linking fertility and cancer

A research team at Kyoto University has discovered STAG3-cohesin, a new mitotic cohesin complex that helps establish the unique DNA architecture of spermaotogonial stem cells (SSCs), the stem cells that give rise to sperm. This "DNA organizer" is crucial for sperm production in mice: without STAG3, SSCs cannot differentiate properly, leading to a fertility problem. In humans, the researchers found that STAG3 is highly expressed in immune B cells and in B-cell lymphomas (a type of blood cancer), and blocking it slowed the growth of these cells. This discovery might open the door to new strategies for treating infertility and certain cancers.

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.

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The surprising reason x-rays can push arthritis patients toward surgery

Routine x-rays aren’t recommended ^[1] to diagnose the condition. Instead, GPs can make a diagnosis based on symptoms and medical history.

Yet nearly half of new patients with knee osteoarthritis who visit a GP in Australia are referred ^[2] for imaging. Osteoarthritis imaging costs ^[3] the health system A$104.7 million each year.

Our new study ^[4] shows using x-rays to diagnose knee osteoarthritis can affect how a person thinks about their knee pain – and can prompt them to consider potentially unnecessary knee replacement surgery.

What happens when you get osteoarthritis?

Osteoarthritis arises from joint changes and the joint working extra hard to repair itself. It affects the entire joint, including the bones, cartilage, ligaments and muscles.

It is most common in older adults, people with a high body weight and those with a history of knee injury.

Many people with knee osteoarthritis experience persistent pain and have difficulties with everyday activities such as walking and climbing stairs.

How is it treated?

In 2021–22, more than 53,000 Australians had knee replacement surgery ^[5] for osteoarthritis.

Hospital services for osteoarthritis, primarily driven by joint replacement surgery, cost ^[6] $3.7 billion in 2020–21.

While joint replacement surgery is often viewed as inevitable for osteoarthritis, it should only be considered ^[7] for those with severe symptoms who have already tried appropriate non-surgical treatments. Surgery carries the risk of serious adverse events ^[8], such as blood clot or infection, and not everyone makes a full recovery.

Most people with knee osteoarthritis can manage it effectively ^[9] with:

education and self-management
exercise and physical activity
weight management (if necessary)
medicines for pain relief (such as paracetamol and non-steroidal anti-inflammatory drugs).

Debunking a common misconception

A common misconception ^[10] is that osteoarthritis is caused by “wear and tear”.

However, research shows ^[11] the extent of structural changes seen in a joint on an x-ray does not reflect the level of pain or disability a person experiences, nor does it predict how symptoms will change.

Some people with minimal joint changes have very bad symptoms, while others with more joint changes have only mild symptoms. This is why routine x-rays aren’t recommended ^[12] for diagnosing knee osteoarthritis or guiding treatment decisions.

Instead, guidelines recommend a “clinical diagnosis” based on a person’s age (being 45 years or over) and symptoms ^[13]: experiencing joint pain with activity and, in the morning, having no joint-stiffness or stiffness that lasts less than 30 minutes.

Despite this, many health professionals in Australia continue to use x-rays to diagnose knee osteoarthritis ^[14]. And many people with osteoarthritis still expect or want them ^[15].

What did our study investigate?

Our study ^[16] aimed to find out if using x-rays to diagnose knee osteoarthritis affects a person’s beliefs about osteoarthritis management, compared to a getting a clinical diagnosis without x-rays.

We recruited 617 people from across Australia and randomly assigned them to watch one of three videos. Each video showed a hypothetical consultation with a general practitioner about knee pain.

One group received a clinical diagnosis of knee osteoarthritis based on age and symptoms, without being sent for an x-ray.

The other two groups had x-rays to determine their diagnosis (the doctor showed one group their x-ray images and not the other).

After watching their assigned video, participants completed a survey about their beliefs about osteoarthritis management.

What did we find?

People who received an x-ray-based diagnosis and were shown their x-ray images had a 36% higher perceived need for knee replacement surgery than those who received a clinical diagnosis (without x-ray).

They also believed exercise and physical activity could be more harmful to their joint, were more worried about their condition worsening, and were more fearful of movement.

Interestingly, people were slightly more satisfied with an x-ray-based diagnosis than a clinical diagnosis.

This may reflect the common misconception that osteoarthritis is caused by “wear and tear” and an assumption that the “damage” inside the joint needs to be seen to guide treatment ^[17].

What does this mean for people with osteoarthritis?

Our findings show why it’s important to avoid unnecessary x-rays when diagnosing knee osteoarthritis.

While changing clinical practice can be challenging, reducing unnecessary x-rays could help ease patient anxiety, prevent unnecessary concern about joint damage, and reduce demand for costly and potentially unnecessary joint replacement surgery.

It could also help reduce exposure to medical radiation and lower health-care costs ^[18].

Previous research in osteoarthritis ^[19], as well as back ^[20] and shoulder ^[21] pain, similarly shows that when health professionals focus on joint “wear and tear” it can make patients more anxious about their condition and concerned about damaging their joints.

If you have knee osteoarthritis, know that routine x-rays aren’t needed for diagnosis or to determine the best treatment for you. Getting an x-ray can make you more concerned and more open to surgery. But there are a range of non-surgical options that could reduce pain, improve mobility and are less invasive.

Written by:

Belinda Lawford
Senior Research Fellow in Physiotherapy, The University of Melbourne
Kim Bennell
Professor of Physiotherapy, The University of Melbourne
Rana Hinman
Professor in Physiotherapy, The University of Melbourne
Travis Haber
Postdoctoral Research Fellow in Physiotherapy, The University of Melbourne

9 in 10 Australian Teachers Are Stressed to Breaking Point

Nine out of 10 Australian teachers are experiencing severe stress, and nearly 70% say their workload is unmanageable, says UNSW Sydney research.

A new study from researchers at UNSW Sydney - the first to examine rates of depression, anxiety and stress in Australian teachers - has found they experience these mental health issues at three times the national norm.

The study 'Teachers' workload, turnover intentions, and mental health' published in Social Psychology of Education surveyed nearly 5000 primary and secondary school teachers across the country.

Researchers found that 90% of teachers reported moderate to extremely severe levels of stress, while more than two-thirds experienced moderate to extremely severe symptoms of depression and anxiety. The figures for depression and anxiety alone are more than double the national averages and point to a profession under immense pressure.

"This is not just a well-being issue - it's a workforce issue," said lead researcher Dr Helena Granziera, from the School of Education at UNSW's Faculty of Arts, Design & Architecture. "Our findings show that teachers are experiencing mental health symptoms at rates far above the general population, and that these symptoms are closely linked to their workload and intentions to leave the profession."

Using validated psychological measures (the DASS test), the study revealed that teachers' average scores for depression, anxiety, and stress were in the "extremely severe" range. Compared to national norms, teachers scored three times higher for depression and nearly four times higher for stress.

Causes of mental health issues

The research also found that workload manageability was a key factor influencing teachers' mental health. Teachers who reported their workload as unmanageable were significantly more likely to experience depressive symptoms, which in turn were strongly associated with their intentions to leave the profession. Notably, 68.8% of teachers described their workload as largely or completely unmanageable.

"Teachers are telling us they're overwhelmed - not by teaching itself, but by the growing burden of non-core tasks," said Dr Granziera. "Administrative duties, compliance requirements, and excessive data collection are taking time away from lesson planning and student engagement. This is leading to burnout and a sense of professional disillusionment."

Impact on education

The study's findings come at a time when Australia is facing a critical teacher shortage. According to recent data from the Australian Institute for Teaching and School Leadership, up to 30% of teachers are considering leaving the profession before retirement age. The results shown in the paper add new urgency to these concerns, showing that poor mental health - particularly depression - is a significant predictor of turnover intentions.

"This research provides clear evidence that improving teachers' working conditions is not just beneficial - it's essential," said Dr Granziera. "If we want to retain skilled educators and ensure quality education for all students, we must address the root causes of teacher stress and mental health decline."

The study also highlighted disparities based on location, with teachers in rural and remote areas reporting higher levels of depressive symptoms. Female teachers were also more likely to report depressive symptoms and turnover intentions, reflecting broader trends in occupational mental health.

What needs to change

In response to these findings, the research team is calling for a multi-pronged approach to support teacher well-being, including:

Policy reforms to reduce non-essential workload and streamline administrative processes
School-level monitoring of teacher well-being and workload
Investment in digital mental health programs tailored for educators, allowing flexible, self-paced support
System-wide interventions to support teacher retention and reduce burnout.

The study took place between October 2022 and May 2024, with recruitment via the Black Dog Institute website and social media channels using targeted social media outreach and teacher-specific platforms.

"This is one of the largest and most comprehensive studies of teacher mental health in Australia," said Dr Granziera. "It provides a clear and urgent message: our teachers are struggling, and they need support."

The implications of these findings extend beyond the classroom. Poor teacher mental health has been linked to lower student achievement, reduced classroom quality, and diminished student well-being.

"Teachers' mental health is intricately related to students' outcomes, both in terms of students' mental health themselves, but also students' academic achievement," says Dr Granziera.

"It's clear improving teacher well-being should be a priority of policy makers not just for teachers but for our education system as a whole."

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