HKU Scientists Unveil Significant Discovery with Potential Impact on Obesity and Osteoporosis Treatments
A team of researchers from The University of Hong Kong (HKU) has made a significant breakthrough in understanding how energy metabolism and bone homeostasis are regulated in mice, which could lead to novel treatments for obesity and osteoporosis. The study, led by Professor Billy CHOW from the School of Biological Sciences (SBS), Faculty of Science, Professor Kelvin YEUNG from the School of Clinical Medicine, LKS Faculty of Medicine, and Professor Will Wei QIAO from the Faculty of Dentistry, along with their colleagues, has been published in the top journal Nature Communications, with Dr Fengwei ZHANG from SBS as the first author. In their pioneering research, the team discover that the hormone secretin, found within the ventromedial hypothalamus (VMH) of the brain, plays a vital role in controlling both energy balance and bone density. This finding challenges the traditional view that secretin's primary function is in the digestive system, showcasing its importance in the central nervous system. Using advanced genetic techniques, the researchers manipulated secretin signalling in mice and observed remarkable outcome. They found that disruptions to secretin pathways in the VMH led to increased appetite, metabolic dysfunctions, and significant bone density loss. Conversely, enhancing secretin signals in the same area increased bone mass without affecting body weight or appetite. ‘Our study opens new doors to treating metabolic and bone diseases. The ability to control appetite and bone density through the brain has significant implications for tackling obesity and osteoporosis,’ notes principal investigator Professor Chow. Looking forward, this research provides new ideas for developing innovative therapies targeting the brain to regulate body metabolism and bone health. The team plans to further investigate the applicability of these findings to human physiology and potential drug development. The University of Hong Kong is known for its interdisciplinary approach, and this research represents a close collaboration between the fields of neuroscience, endocrinology, and orthopedics. Details can be found at Nature Communications under the title ‘Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice’. The journal paper can be accessed here. Click here to learn more about Professor Billy Chow and his research group. Click here to learn more about Professor Kelvin Yeung and his research group. Click here to learn more about Professor Will Wei Qiao and his research group.
NEWS DETAIL
Cracking Epigenetic Inheritance: HKU Biologists Discovered the Secrets of How Gene Traits are Passed on
A research team led by Professor Yuanliang ZHAI at the School of Biological Sciences, The University of Hong Kong (HKU) collaborating with Professor Ning GAO and Professor Qing LI from Peking University (PKU), as well as Professor Bik-Kwoon TYE from Cornell University, has recently made a significant breakthrough in understanding how the DNA copying machine helps pass on epigenetic information to maintain gene traits at each cell division. Understanding how this coupled mechanism could lead to new treatments for cancer and other epigenetic diseases by targeting specific changes in gene activity. Their findings have recently been published in Nature. Background of the Research Our bodies are composed of many differentiated cell types. Genetic information is stored within our DNA which serves as a blueprint guiding the functions and development of our cells. However, not all parts of our DNA are active at all times. In fact, every cell type in our body contains the same DNA, but only specific portions are active, leading to distinct cellular functions. For example, identical twins share nearly identical genetic material but exhibit variations in physical characteristics, behaviours and disease susceptibility due to the influence of epigenetics. Epigenetics functions as a set of molecular switches that can turn genes on or off without altering the DNA sequence. These switches are influenced by various environmental factors, such as nutrition, stress, lifestyle, and environmental exposures. In our cells, DNA is organised into chromatin. The nucleosome forms a fundamental repeating unit of chromatin. Each nucleosome consists of approximately 147 base pairs of DNA wrapped around a histone octamer which is composed of two H2A-H2B dimers and one H3-H4 tetramer. During DNA replication, parental nucleosomes carrying the epigenetic tags, also known as histone modifications, are dismantled and recycled, ensuring the accurate transfer of epigenetic information to new cells during cell division. Errors in this process can alter the epigenetic landscape, gene expression and cell identity, with potential implications for cancer and ageing. Despite extensive research, the molecular mechanism by which epigenetic information is passed down through the DNA copying machine, called the replisome, remains unclear. This knowledge gap is primarily due to the absence of detailed structures that capture the replisome in action when transferring parental histones with epigenetic tags. Studying the process is challenging because of the fast-paced nature of chromatin replication, as it involves rapid disruption and restoration of nucleosomes to keep up with the swift DNA synthesis. In previous studies, the research team made significant progress in understanding the DNA copying mechanism, including determining the structures of various replication complexes. These findings laid a solid foundation for the current research on the dynamic process of chromatin duplication. Summary of Research Findings This time, the team achieved another breakthrough by successfully capturing a key snapshot of parental histone transfer at the replication fork. They purified endogenous replisome complexes from early-S-phase yeast cells on a large scale and utilised cryo-electron microscopy (cryo-EM) for visualisation. They found that a chaperone complex FACT (consisting of Spt16 and Pob3) interacts with parental histones at the front of the replisome during the replication process. Notably, they observed that Spt16, a component of FACT, captures the histones that have been completely stripped off the duplex DNA from the parental nucleosome. The evicted histones are preserved as a hexamer, with one H2A-H2B dimer missing. Another protein that involved in DNA replication, Mcm2, takes the place of the missing H2A-H2B dimer on the vacant site of the parental histones, placing the FACT-histone complex onto the front bumper of the replisome engine, called Tof1. This strategic positioning of histone hexamer on Tof1 by Mcm2 facilitates the subsequent transfer of parental histones to the newly synthesised DNA strands. These findings provide crucial insights into the mechanism that regulates parental histone recycling by the replisome to ensure the faithful propagation of epigenetic information at each cell division. This study, led by Professor Zhai, involved a collaborative effort that spanned nearly eight years, starting at HKUST and concluding at HKU. He expressed his excitement about the findings, ‘It only took us less than four months from submission to Nature magazine to the acceptance of our manuscript. The results are incredibly beautiful. Our cryo-EM structures offer the first visual glimpse into how the DNA copying machine and FACT collaborate to transfer parental histone at the replication fork during DNA replication. This knowledge is crucial for elucidating how epigenetic information is faithfully maintained and passed on to subsequent generations. But, there is still much to learn. As we venture into uncharted territory, each new development in this field will represent a big step forward for the study of epigenetic inheritance.’ The implications of this research extend beyond understanding epigenetic inheritance. Scientists can now explore gene expression regulation, development, and disease with greater depth. Moreover, this breakthrough opens up possibilities for targeted therapeutic interventions and innovative strategies to modulate epigenetic modifications for cancer treatment. As the scientific community delves deeper into the world of epigenetics, this study represents a major step towards unravelling the complexities of replication-coupled histone recycling. The cryo-EM structure of the yeast replisome in complex with FACT and parental histones (A) and its atomic model (B). Modified from Li et al, Nature (2024) The evicted histone hexamer and its chaperons from the replisome structure. (A-B) The architecture of the parental histone hexamer. (C-D) The histone-chaperone complex on the replisome. (E-F) The structure of an intact nucleosome. Modified from Li et al, Nature (2024) About the Research Team Apart from Professor Yuanliang Zhai’s lab, the research team also includes Professor Xiang David Li from Department of Chemistry of HKU, Professor Yang Liu and Professor Keda Zhou from School of Biomedical Sciences of HKU, Professor Shangyu Dang from Division of Life Science of HKUST, and others. Learn more about Professor Yuanliang Zhai’s work and his research team: https://www.scifac.hku.hk/people/zhai-yuanliang or https://zhai95.wixsite.com/mysite-1 Co-authors include Mr Yuan Gao, Mr Jian Li, Dr Zhichun Xu from School of Biological Sciences (SBS) of HKU; Dr Ningning Li, Ms Yujie Zhang, Dr Jianxun Feng from School of Life Sciences of PKU, Dr Daqi Yu and Dr Jianwei Lin from Department of Chemistry of HKU, and Dr Yingyi ZHANG from Biological Cryo- EM Center of HKUST. The journal paper can be accessed here.
NEWS DETAIL