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Figure 1. Diverse marine life (crinoid, octocorals and sponges) on a seamount off the Pacific coast of Costa Rica. Photo credit: Schmidt Ocean Institute, FK190106, Erik Cordes Chief Scientist

HKU Marine Scientist contributes to research assessing the potential risks of ocean-based climate intervention technologies on deep-sea ecosystems

The deep sea is one of the least well-known areas on Earth, comprising multiple vulnerable ecosystems that play critical roles in the carbon cycle. However, the deep sea is directly exposed to the effects of human-induced climate change and may now face additional challenges arising from efforts to counteract climate change artificially. These efforts have evolved into geoengineering solutions that could operate on vast spatial scales. Ocean-based climate interventions (OBCIs) are increasingly claimed as promising solutions to mitigate climate change. These interventions use different technologies to remove carbon dioxide (CO2) from the atmosphere and sequester the carbon in the deep sea, manage solar radiation, or produce renewable energy.  However, little is known about the impacts of OBCI technologies on ocean biogeochemistry and the biodiversity of ocean ecosystems. This is true in particular for deep-sea ecosystems, which cover over 40% of the Earth and contain highly vulnerable species and ecosystems. An international team of experts convened remotely as part of the Deep Ocean Stewardship Initiative’s Climate Working Group to consider the deep-sea impacts of OBCI. A research team led by Dr Lisa LEVIN from the Scripps Institution of Oceanography, UC San Diego, including Dr Moriaki YASUHARA from the School of Biological Sciences and The Swire Institute of Marine Science, The University of Hong Kong (HKU), has analysed the proposed approaches to assess their potential impacts on deep-sea ecosystems and biodiversity. Their findings were recently reported in the scientific journal Science raise substantial concern on the potential impacts of these technologies on deep-sea ecosystems and call for the need for an integrated research effort to carefully assess the cost and benefits of each intervention.  The research findings highlight the potential impacts of OBCIs on deep-sea ecosystems. Several lines of evidence led experts to raise substantial concern and call for the need for an integrated research framework to consider deep-sea impacts carefully in mitigation planning. Visual summary of OBCIs. Image credit: Sarah Seabrook. Balancing hope and risk While the growing interest in OBCIs as potential tools to mitigate the impacts may provide some hope for a sustainable future, the potential environmental impacts and effectiveness at full-scale have not been evaluated sufficiently. Additionally, governance of OBCI activities is also in the early stages, posing risks to deep-sea biodiversity and ecosystems. For example, one such intervention is direct CO2 injection into the deep sea, which could sequester large amounts of carbon dioxide from the atmosphere and reduce the overall concentration of greenhouse gases. However, while direct CO2 injection holds promise as a climate intervention, it also carries significant risks. One potential risk is the development of hypercapnia, a condition that occurs when the concentration of carbon dioxide in the water exceeds certain thresholds, which can have negative impacts on marine life and ecosystems. Other carbon sequestration technologies such as ocean fertilisation (enhancing phytoplankton production in the surface ocean and resulting their deposition on the deep ocean floor) and crop waste deposition (deep-sea disposal of terrestrial crop waste), the ideas putting carbon as phytoplankton or terrestrial plant bodies into deep-sea, could also change the food and oxygen availability for deep-sea life. The deep sea is facing unprecedented threats due to the impact of industrial fisheries, pollution, warming, deoxygenation, acidification and other climate-change-related problems. OBCIs could add further pressure and threaten the functioning of these systems, which are essential for the entire planet. The lead author Lisa Levin says, ‘I see open ocean-based climate intervention as a rapidly emerging arena that poses significant challenges for deep-ocean ecosystems, and thus demands new science and governance before we commit to action.’ ‘Especially given the vastness, vulnerability, comparatively pristine nature, and poor scientific understanding of the deep-sea ecosystem, we should be careful to green-light these activities that could have irreversible impacts.’ Moriaki Yasuhara continues. The interventions in the marine environment may be irreversible, and more research is needed to assess their impact. Prior to deploying geo-engineered solutions on a large-scale, we should at least understand what those pressures will be, and, by consequence, what the deep-sea may look like in the future. The journal paper can be addressed here A field of sea pens on a seamount off the Pacific Coast of Costa Rica. Photo credit:  Schmidt Ocean Institute, FK190106, Erik Cordes Chief Scientist.        

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The team found that RIF1-PP1 prevents BLM from unwinding the ultrafine DNA bridges.  Image Credit: Dr Gary Ying Wai CHAN.

Targeting DNA bridges: HKU Biologists Uncover key to preserve genome integrity Enhancing the understanding of cancer development

A research team led by Dr Gary Ying Wai CHAN from the School of Biological Sciences at The University of Hong Kong (HKU), has uncovered a new mechanism that ensures correct DNA segregation in cell division, where improper cell division will lead to the development of cancer. The team's findings, published in the journal Cell Reports, focus on the roles of two proteins, RIF1 and protein phosphatase 1 (PP1), in resolving ultrafine DNA bridges. These bridges are formed when sister chromatids are connected by DNA joint molecules during mitosis. If these DNA bridges cannot be resolved or removed properly, they will eventually break and cause DNA damage in the daughter cells, which can lead to the development of cancer cells. The process of Mitosis A human life begins with a single cell – the fertilised egg. This single cell needs to replicate and divide into approximately 37 trillion cells. The process by which a cell replicates its DNA then equally segregates into two identical cells is known as mitosis, which is a vital process for growth and replacing worn out cells. However, equal segregation of DNA is one of the most challenging tasks in mitosis. Our DNA is organised into 23 pairs of chromosomes, each of which is replicated into two sister chromatids. During mitosis, these sister chromatids are separated into two identical daughter cells. They are often connected by DNA joint molecules, which can form long fine DNA threads known as ultrafine DNA bridges when the two sister chromatids are separating under a pulling force. If these DNA bridges cannot be resolved or removed properly, they will eventually break, causing damage in the daughter cells. In a worst-case scenario, this DNA damage can potentially lead to the development of cancer. To elucidate the detailed mechanism of how cells resolve the DNA bridges, the team led by Dr Gary Ying Wai Chan uncovered the roles of two proteins, RIF1 and protein phosphatase 1 (PP1) in regulating the resolution of ultrafine DNA bridges. The role of RIF1 and PP1 in resolving DNA bridges In 2007, two research groups led by Professor Erich NIGG and Professor Ian HICKSON discovered the existence of ultrafine DNA bridges by identifying the first two ultrafine bridge-binding proteins, PICH and BLM. Later on, RIF1 was also identified as a bridge-binding protein. It is known that PICH is the first protein recognising the DNA bridges, then it recruits BLM and RIF1 to ultrafine DNA bridges; however, the exact mechanism by which these bridge-binding proteins work to resolve the bridges remains unclear. To understand the role of RIF1 in resolving DNA bridges, the research team employed a revolutionary genome editing technology, the CRISPR/Cas9, to deplete RIF1 in a cell model during mitosis. During which, the team found that loss of RIF1 leads to increased formation of DNA damage and micronuclei due to breakage of ultrafine DNA bridges, as our data suggest that RIF1 plays a crucial role in preventing double-stranded DNA bridges from converting into single-stranded DNA, which is more susceptible to breakage. RIF1 was found to achieve this by recruiting PP1, a protein phosphatase, which reduces the interaction between BLM and PICH and thereby reduces the amount of BLM on the bridges, which the team discovered that is responsible for unwinding the bridge DNA to single-stranded DNA. Finally, the double-stranded DNA bridges protected by RIF1-PP1 are believed to be resolved by another enzyme known as topoisomerase IIα, which could mediate double-stranded DNA decatenation to ensure proper DNA segregation. This research not only sheds light on the novel regulatory mechanism by which RIF1-PP1 facilitates the resolution of DNA bridges, but also reveals how ultrafine DNA bridges can induce DNA damage and genome instability if they are not properly resolved. The findings suggest that DNA bridge-binding proteins may serve as potential therapeutic targets for the development of anticancer drugs, as DNA bridges are considered a source of genome instability that drives tumorigenesis. ‘The discovery that RIF1 recruits PP1 to the bridges is the first step in understanding how the resolution of ultrafine DNA bridges is regulated by protein phosphorylation/dephosphorylation,’ said Dr Gary CHAN. ‘The next step is to identify the target substrates of the RIF1-PP1 complex, which can advance our understanding of how different bridge-binding proteins interact with each other and may lead to the identification of new therapeutic targets for cancer.’ The journal paper, entitled ‘RIF1 Suppresses the Formation of Single-Stranded Ultrafine Anaphase Bridges via Protein Phosphatase 1’, can be found here.  Click here to learn more about the work of Dr Ying Wai Chan and his research team.   

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Our alumnus Dr Colin LUK and his business partner founded this quality assurance company isoFoodtrace, using stable isotope analysis to trace the roots of what we eat.

Alumni Series - Tracing the Roots of Food with Stable Isotope Analysis

Food has always been fundamental to human life, connecting people to their roots, culture, and memories. As globalisation increases and food fraudulent concerns mount, tracing the journey of food from farm to table has become increasingly important. Faced with these challenges, two visionary PhD graduates from The School of Biological Sciences founded IsoFoodtrace, a company utilising stable isotope analysis, a food traceability technology, to provide a reliable and efficient platform for tracking food products’ origin and journey. IsoFoodtrace verifies food product attributes and labels, enabling unparalleled assurance in global food systems. By directly testing end products, their fast and cost-efficient methods allow consumers to know exactly what they buy. Let us explore the pioneering journeys of these young entrepreneurs driving unprecedented assurance in our food systems.   Dr Colin Luk and Dr David Baker. Meeting during their PhD studies in 2014, Inga CONTI-JERPE investigated coral nutrition using stable isotope analysis while Colin LUK studied forest recovery using Arthropods indicators. At that point, Colin had over ten years of F&B experience with concerns about food origin. He recalled, ‘I discussed using stable isotope analysis to detect food fraud with Inga, and we both think it’s doable. At the same time, HKU iDendron had just initiated a start-up SEED program while Science Park offered a 100K start-up grant—it seemed a good opportunity for us to build a start-up.’ With the support of Dr David BAKER, the Director of HKU Conservative Forensic Laboratory, and the consultation from Dr Jetty LEE, the Programme Director of the HKU MSc Food Industry: Management & Marketing, they piloted testing supermarket wild salmon and wrote a business proposal for funding, enabling them to launch IsoFoodtrace, a real business tackling food fraud.  Empowering Consumers to Make Informed Choices Dr Colin Luk at the Stable Isotope Laboratory of HKU Stable isotope ratios vary with food attributes like farming practices, feed, and origin. For example, wild salmon has more 15N (Nitrogen) than farmed, and cattle feed diets (grass vs grain) affect 13C (Carbon) ratios. Using Stable Isotope Ratio Mass Spectrometry, foods are chemically analysed and isotopes measured. Once the stable isotope signatures have been detected, they are then compared against a reference database; hence, the origin and composition of a food sample can be determined. This cutting-edge technology can ensure food safety and authenticity, giving customers peace of mind.. In just two years, IsoFoodtrace has grown to a team of 11. In the long term, it aims to build a global food stable isotope database enabling verification of production and origin claims. Colin said, ‘We aim not only to battle fraudulent claims of food quality but also to contribute to better food safety and sustainability by allowing businesses and consumers to make more informed purchases.’ Through their innovative approach to food tracing, they have revealed the complex processes involved in food production and distribution. Though now relocated to the US, Inga continues working with Colin to grow the business, she said, ‘Food safety is of paramount importance in today's globalised food systems. By tracing the roots of food, I hope we can eventually empower consumers to make informed choices and holds businesses accountable for authentic claims.’ As consumers, we can all play a role in supporting their efforts by seeking out products that have been verified and demanding greater transparency in the food industry. By doing so, we can help to build a safer and more sustainable food system for all.   Dr Colin Chung-lim LUK PhD in Biological Sciences Project Development Lead@isoFoodtrace     Dr Inga E. CONTI-JERPE Scientific Development Lead@isoFoodtrace Biological Researcher at University of California, Berkely                

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Figure 1. Diverse marine life (crinoid, octocorals and sponges) on a seamount off the Pacific coast of Costa Rica. Photo credit: Schmidt Ocean Institute, FK190106, Erik Cordes Chief Scientist

HKU Marine Scientist contributes to research assessing the potential risks of ocean-based climate intervention technologies on deep-sea ecosystems

The deep sea is one of the least well-known areas on Earth, comprising multiple vulnerable ecosystems that play critical roles in the carbon cycle. However, the deep sea is directly exposed to the effects of human-induced climate change and may now face additional challenges arising from efforts to counteract climate change artificially. These efforts have evolved into geoengineering solutions that could operate on vast spatial scales. Ocean-based climate interventions (OBCIs) are increasingly claimed as promising solutions to mitigate climate change. These interventions use different technologies to remove carbon dioxide (CO2) from the atmosphere and sequester the carbon in the deep sea, manage solar radiation, or produce renewable energy.  However, little is known about the impacts of OBCI technologies on ocean biogeochemistry and the biodiversity of ocean ecosystems. This is true in particular for deep-sea ecosystems, which cover over 40% of the Earth and contain highly vulnerable species and ecosystems. An international team of experts convened remotely as part of the Deep Ocean Stewardship Initiative’s Climate Working Group to consider the deep-sea impacts of OBCI. A research team led by Dr Lisa LEVIN from the Scripps Institution of Oceanography, UC San Diego, including Dr Moriaki YASUHARA from the School of Biological Sciences and The Swire Institute of Marine Science, The University of Hong Kong (HKU), has analysed the proposed approaches to assess their potential impacts on deep-sea ecosystems and biodiversity. Their findings were recently reported in the scientific journal Science raise substantial concern on the potential impacts of these technologies on deep-sea ecosystems and call for the need for an integrated research effort to carefully assess the cost and benefits of each intervention.  The research findings highlight the potential impacts of OBCIs on deep-sea ecosystems. Several lines of evidence led experts to raise substantial concern and call for the need for an integrated research framework to consider deep-sea impacts carefully in mitigation planning. Visual summary of OBCIs. Image credit: Sarah Seabrook. Balancing hope and risk While the growing interest in OBCIs as potential tools to mitigate the impacts may provide some hope for a sustainable future, the potential environmental impacts and effectiveness at full-scale have not been evaluated sufficiently. Additionally, governance of OBCI activities is also in the early stages, posing risks to deep-sea biodiversity and ecosystems. For example, one such intervention is direct CO2 injection into the deep sea, which could sequester large amounts of carbon dioxide from the atmosphere and reduce the overall concentration of greenhouse gases. However, while direct CO2 injection holds promise as a climate intervention, it also carries significant risks. One potential risk is the development of hypercapnia, a condition that occurs when the concentration of carbon dioxide in the water exceeds certain thresholds, which can have negative impacts on marine life and ecosystems. Other carbon sequestration technologies such as ocean fertilisation (enhancing phytoplankton production in the surface ocean and resulting their deposition on the deep ocean floor) and crop waste deposition (deep-sea disposal of terrestrial crop waste), the ideas putting carbon as phytoplankton or terrestrial plant bodies into deep-sea, could also change the food and oxygen availability for deep-sea life. The deep sea is facing unprecedented threats due to the impact of industrial fisheries, pollution, warming, deoxygenation, acidification and other climate-change-related problems. OBCIs could add further pressure and threaten the functioning of these systems, which are essential for the entire planet. The lead author Lisa Levin says, ‘I see open ocean-based climate intervention as a rapidly emerging arena that poses significant challenges for deep-ocean ecosystems, and thus demands new science and governance before we commit to action.’ ‘Especially given the vastness, vulnerability, comparatively pristine nature, and poor scientific understanding of the deep-sea ecosystem, we should be careful to green-light these activities that could have irreversible impacts.’ Moriaki Yasuhara continues. The interventions in the marine environment may be irreversible, and more research is needed to assess their impact. Prior to deploying geo-engineered solutions on a large-scale, we should at least understand what those pressures will be, and, by consequence, what the deep-sea may look like in the future. The journal paper can be addressed here A field of sea pens on a seamount off the Pacific Coast of Costa Rica. Photo credit:  Schmidt Ocean Institute, FK190106, Erik Cordes Chief Scientist.        

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The team found that RIF1-PP1 prevents BLM from unwinding the ultrafine DNA bridges.  Image Credit: Dr Gary Ying Wai CHAN.

Targeting DNA bridges: HKU Biologists Uncover key to preserve genome integrity Enhancing the understanding of cancer development

A research team led by Dr Gary Ying Wai CHAN from the School of Biological Sciences at The University of Hong Kong (HKU), has uncovered a new mechanism that ensures correct DNA segregation in cell division, where improper cell division will lead to the development of cancer. The team's findings, published in the journal Cell Reports, focus on the roles of two proteins, RIF1 and protein phosphatase 1 (PP1), in resolving ultrafine DNA bridges. These bridges are formed when sister chromatids are connected by DNA joint molecules during mitosis. If these DNA bridges cannot be resolved or removed properly, they will eventually break and cause DNA damage in the daughter cells, which can lead to the development of cancer cells. The process of Mitosis A human life begins with a single cell – the fertilised egg. This single cell needs to replicate and divide into approximately 37 trillion cells. The process by which a cell replicates its DNA then equally segregates into two identical cells is known as mitosis, which is a vital process for growth and replacing worn out cells. However, equal segregation of DNA is one of the most challenging tasks in mitosis. Our DNA is organised into 23 pairs of chromosomes, each of which is replicated into two sister chromatids. During mitosis, these sister chromatids are separated into two identical daughter cells. They are often connected by DNA joint molecules, which can form long fine DNA threads known as ultrafine DNA bridges when the two sister chromatids are separating under a pulling force. If these DNA bridges cannot be resolved or removed properly, they will eventually break, causing damage in the daughter cells. In a worst-case scenario, this DNA damage can potentially lead to the development of cancer. To elucidate the detailed mechanism of how cells resolve the DNA bridges, the team led by Dr Gary Ying Wai Chan uncovered the roles of two proteins, RIF1 and protein phosphatase 1 (PP1) in regulating the resolution of ultrafine DNA bridges. The role of RIF1 and PP1 in resolving DNA bridges In 2007, two research groups led by Professor Erich NIGG and Professor Ian HICKSON discovered the existence of ultrafine DNA bridges by identifying the first two ultrafine bridge-binding proteins, PICH and BLM. Later on, RIF1 was also identified as a bridge-binding protein. It is known that PICH is the first protein recognising the DNA bridges, then it recruits BLM and RIF1 to ultrafine DNA bridges; however, the exact mechanism by which these bridge-binding proteins work to resolve the bridges remains unclear. To understand the role of RIF1 in resolving DNA bridges, the research team employed a revolutionary genome editing technology, the CRISPR/Cas9, to deplete RIF1 in a cell model during mitosis. During which, the team found that loss of RIF1 leads to increased formation of DNA damage and micronuclei due to breakage of ultrafine DNA bridges, as our data suggest that RIF1 plays a crucial role in preventing double-stranded DNA bridges from converting into single-stranded DNA, which is more susceptible to breakage. RIF1 was found to achieve this by recruiting PP1, a protein phosphatase, which reduces the interaction between BLM and PICH and thereby reduces the amount of BLM on the bridges, which the team discovered that is responsible for unwinding the bridge DNA to single-stranded DNA. Finally, the double-stranded DNA bridges protected by RIF1-PP1 are believed to be resolved by another enzyme known as topoisomerase IIα, which could mediate double-stranded DNA decatenation to ensure proper DNA segregation. This research not only sheds light on the novel regulatory mechanism by which RIF1-PP1 facilitates the resolution of DNA bridges, but also reveals how ultrafine DNA bridges can induce DNA damage and genome instability if they are not properly resolved. The findings suggest that DNA bridge-binding proteins may serve as potential therapeutic targets for the development of anticancer drugs, as DNA bridges are considered a source of genome instability that drives tumorigenesis. ‘The discovery that RIF1 recruits PP1 to the bridges is the first step in understanding how the resolution of ultrafine DNA bridges is regulated by protein phosphorylation/dephosphorylation,’ said Dr Gary CHAN. ‘The next step is to identify the target substrates of the RIF1-PP1 complex, which can advance our understanding of how different bridge-binding proteins interact with each other and may lead to the identification of new therapeutic targets for cancer.’ The journal paper, entitled ‘RIF1 Suppresses the Formation of Single-Stranded Ultrafine Anaphase Bridges via Protein Phosphatase 1’, can be found here.  Click here to learn more about the work of Dr Ying Wai Chan and his research team.   

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Our alumnus Dr Colin LUK and his business partner founded this quality assurance company isoFoodtrace, using stable isotope analysis to trace the roots of what we eat.

Alumni Series - Tracing the Roots of Food with Stable Isotope Analysis

Food has always been fundamental to human life, connecting people to their roots, culture, and memories. As globalisation increases and food fraudulent concerns mount, tracing the journey of food from farm to table has become increasingly important. Faced with these challenges, two visionary PhD graduates from The School of Biological Sciences founded IsoFoodtrace, a company utilising stable isotope analysis, a food traceability technology, to provide a reliable and efficient platform for tracking food products’ origin and journey. IsoFoodtrace verifies food product attributes and labels, enabling unparalleled assurance in global food systems. By directly testing end products, their fast and cost-efficient methods allow consumers to know exactly what they buy. Let us explore the pioneering journeys of these young entrepreneurs driving unprecedented assurance in our food systems.   Dr Colin Luk and Dr David Baker. Meeting during their PhD studies in 2014, Inga CONTI-JERPE investigated coral nutrition using stable isotope analysis while Colin LUK studied forest recovery using Arthropods indicators. At that point, Colin had over ten years of F&B experience with concerns about food origin. He recalled, ‘I discussed using stable isotope analysis to detect food fraud with Inga, and we both think it’s doable. At the same time, HKU iDendron had just initiated a start-up SEED program while Science Park offered a 100K start-up grant—it seemed a good opportunity for us to build a start-up.’ With the support of Dr David BAKER, the Director of HKU Conservative Forensic Laboratory, and the consultation from Dr Jetty LEE, the Programme Director of the HKU MSc Food Industry: Management & Marketing, they piloted testing supermarket wild salmon and wrote a business proposal for funding, enabling them to launch IsoFoodtrace, a real business tackling food fraud.  Empowering Consumers to Make Informed Choices Dr Colin Luk at the Stable Isotope Laboratory of HKU Stable isotope ratios vary with food attributes like farming practices, feed, and origin. For example, wild salmon has more 15N (Nitrogen) than farmed, and cattle feed diets (grass vs grain) affect 13C (Carbon) ratios. Using Stable Isotope Ratio Mass Spectrometry, foods are chemically analysed and isotopes measured. Once the stable isotope signatures have been detected, they are then compared against a reference database; hence, the origin and composition of a food sample can be determined. This cutting-edge technology can ensure food safety and authenticity, giving customers peace of mind.. In just two years, IsoFoodtrace has grown to a team of 11. In the long term, it aims to build a global food stable isotope database enabling verification of production and origin claims. Colin said, ‘We aim not only to battle fraudulent claims of food quality but also to contribute to better food safety and sustainability by allowing businesses and consumers to make more informed purchases.’ Through their innovative approach to food tracing, they have revealed the complex processes involved in food production and distribution. Though now relocated to the US, Inga continues working with Colin to grow the business, she said, ‘Food safety is of paramount importance in today's globalised food systems. By tracing the roots of food, I hope we can eventually empower consumers to make informed choices and holds businesses accountable for authentic claims.’ As consumers, we can all play a role in supporting their efforts by seeking out products that have been verified and demanding greater transparency in the food industry. By doing so, we can help to build a safer and more sustainable food system for all.   Dr Colin Chung-lim LUK PhD in Biological Sciences Project Development Lead@isoFoodtrace     Dr Inga E. CONTI-JERPE Scientific Development Lead@isoFoodtrace Biological Researcher at University of California, Berkely                

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A new study conducted by HKU biologists and collaborators sheds light on sodium regulation mechanisms.

HKU biologists and collaborators reveal a gut-brain pathway that regulates sodium appetite

A research team led by Professor Billy KC CHOW from the School of Biological Sciences at the University of Hong Kong (HKU), in collaboration with Professor Li ZHANG, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, has uncovered a new mechanism of the Secretin (SCT) in regulating water and sodium homeostasis, which demonstrates a gut-brain pathway that initiates sodium appetite and illustrates the function of colon released SCT. The study has recently been published in a top journal– Science Advances. Understanding sodium homeostasis in the body Water and salt homeostasis is one of the three fundamental homeostasis for mammals to maintain body metabolism. The disorder of water and sodium homeostasis will lead to hypernatremia and hyponatremia, leading to serious organ dysfunction, including muscles and the brain. Thus, sophisticated neural and endocrine pathways are formed to regulate water and sodium balance during evolution. Water and sodium homeostasis contain reabsorption, water consumption, and sodium appetite. The kidney controls peripheral water and sodium reabsorption mainly by the Renin-angiotensin-aldosterone system (RAAS), while water and sodium intake is tightly controlled in the brain. Circumventricular organs play vital roles in modulating water consumption, while the nucleus of the solitary tract (NTS) regulates sodium appetite. Compared with plenty of studies that have unravelled water intake regulation in the brain, only a few studies focus on neuron pathways that regulate sodium appetite. In the brain, HSD2-positive neurons in NTS and AT1a-positive neurons in the subfornical organ (SFO) initiate sodium intake separately, while the intestine and colon take responsibility for sodium uptake. Thus, understanding gut-brain cooperation will help in better constructing complete neural pathways. Through constant effort, our research team identified and confirmed a novel pathway that colon-released SCT activates NTS SCTR+ neurons, which project to the paraventricular nucleus of the hypothalamus (PVH) that takes responsibility for SCT-derived sodium metabolism. This study helps to better understand the peripheral-central cooperation that modulates sodium intake. Research Background SCT, a short peptide with only 27 amino acids, is the first identified hormone founded by William Bayliss and Ernest Starling in 1902, which regulates a wide range of systems in mammals, including gastrointestinal, cardiovascular, and central nervous systems. The SCT function is tightly connected to the SCT receptor (SCTR). As one of a class B GPCR, the signalling pathway of SCTR is closely connected with cyclic adenosine monophosphate (cAMP) and inositol triphosphate (IP3). The result from the human protein atlas shows SCTR has a high expression level in the respiratory system, GI tract, pancreas, and kidney. Some brain regions, such as NTS and the cerebral cortex, were also found SCTR expression. When acid chyme enters the duodenum, SCT is released to the bloodstream or intestinal lumen and detected by the pancreas SCTR. The pancreas then secretes pancreatic fluid full of bicarbonate, which neutralizes the acid from the stomach and protects the intestine. In the cardiovascular system, SCT and SCTR can regulate blood pressure, cardiac blood flow, and plasma NO concentration. In the central nervous system, SCT mediates motor learning behaviour, initiates water intake, and inhibits food intake. Key findings Here, we revealed a gut-brain pathway in which a gastrointestinal hormone, secretin released from colon endocrine cells under body sodium deficiency condition, is indispensable for initiating salt appetite. Peripheral SCT penetrates the blood-brain barrier and enters cerebrospinal fluid. As the neural substrate, SCT activates specific receptors in the NTS, which further project to the downstream paraventricular nucleus of the hypothalamus (PVH), resulting in enhanced sodium intake. These results demonstrated a previously unrecognized gut-brain pathway for the timely regulation of sodium homeostasis. Our results also have potential values in clinical fields, as ileostomy patients showed chronic salt and water disorders, together with low urinary sodium excretion, all of which are similar to the mice under sodium deficiency conditions. Such clinical observations can be replicated in animal models, as previous studies indicated SCT expression increased within 24 hours after colectomy and decreased significantly on day 14 in rats. Although no direct evidence has been provided for the role of colon-SCT in sodium homeostasis in human patients, these studies did imply its possible involvement. Further work can be performed to explore the possibility of targeting SCT-SCTR for correcting sodium imbalance in colectomy patients. The journal paper can be accessed here.   About the research team The research was conducted by the team led by Professor Billy KC Chow from HKU School of Biological Sciences. Dr Yuchu LIU from Professor Chow’s team is the first author of the paper. Professor Li Zhang is the co-corresponding author, and his team make a great effort in this study. The research has been supported by three grants from the Research Grants Council of Hong Kong and the National Natural Science Foundation of China. This study was supported by the Research Grants Council of Hong Kong GRF HKU17113120, HKU17127718, and the National Natural Science Foundation of China 32070955. About Professor Billy Chow Professor Billy K. C. Chow is the Chair of Endocrinology at the School of Biological Sciences, HKU. His expertise lies in GPCR and ligand interactions, eventually leading to deciphering the physiologic actions of GPCRs and identifying novel GPCR agonists/antagonists as therapeutic solutions. He is the founder of an HKU spin-off company PhrmaSec Ltd, which aims to translate basic research into societal impact by targeting GPCRs. 

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Figure 1. HKU Chemical Biologists decode a histone mark important for gene regulation program that go awry in cancer. The research team members include: (from left) Dr Yuanliang ZHAI, Dr Jason Wing Hon WONG, Dr Xiucong BAO and Professor Xiang David LI.

HKU Chemical Biologists decode a histone mark important for gene regulation program that go awry in cancer

A research team from the University of Hong Kong (HKU) led by Professor Xiang David LI from the Department of Chemistry in collaboration with Dr Yuanliang ZHAI from the HKU School of Biological Sciences and Dr Jason Wing Hon WONG and Dr Xiucong BAO from the HKU School of Biomedical Sciences (Figure 1) recently made a key breakthrough in understanding how genetic information encoded in our DNA is “read” and why errors in “reading” such information can often lead to developmental defects or cancers. The findings were recently published in Science. Each type of cell in the human body (with some exceptions) contains exactly the same DNA sequence known as genes. Therefore, to make a specific cell type (e.g., a stem cell, a neuron), each cell needs to carefully “choose” which genes to express. This fundamental process is regulated by diverse modifications of histone proteins, which were previously thought as mere spools for packaging DNA in the nucleus of our cells. We now know that these histone modifications are tags or marks on chromatin that function as master switches for the regulation of genes—they determine which sets of genes in a cell should be “ON” or “OFF” at the right time and to the right extent. Misregulation of this fundamental process underlies many severe human diseases such as cancers. Different types of histone marks act as cellular signals to control various chromatin-associated machineries that regulate gene expression, DNA replication, and damage repair. One of the challenges in chromatin biology is how particular histone marks are interpreted to achieve their biological function. To answer this question, it is essential to find the “readers”, a class of proteins that recognise specific histone marks and “translate” them by turning the expression of genes up or down accordingly. However, “readers” of many histone marks are still unknown, which limits our ability to understand their roles in gene regulation. A long-standing interest of Professor Li’s lab is the development of novel chemical approaches to identify histone “readers” that might be difficult to find using traditional biological methods. One such method uses a peptide containing a histone mark (i.e., a small fragment of histone protein) that acts as the “bait” to “fish” for “readers” that recognise the mark. ‘The key to success is not only the “bait” but also a specially designed “hook” that is equipped with a light-activated chemical group to capture the “readers” upon exposure to UV light,’ explains Professor Li.   In this study, the team focused on a methylation mark at histone H3 lysine 79 (H3K79me2). In human cells, this mark is found in actively expressed genes. Loss of H3K79me2 in mammalian embryos can lead to multiple developmental abnormalities, including impaired growth, cardiac dilation, and death. On the other hand, H3K79me2 has been found at abnormally high levels and in the wrong places (e.g., cancer-promoting genes) in a variety of cancers such as childhood leukaemia.  Despite its biological significance in gene regulation, the mechanism of how this mark is “translated” is unclear, as the “readers” of H3K79me2 have not been found since its discovery 20 years ago. In fact, over the years, many labs have tried various approaches to look for these “readers”. ‘It is a great challenge to identify H3K79me2 “readers”, even with our previously developed novel chemical approaches,’ says Professor Li. There are two major hurdles to overcome. First, “reading” the marks may involve not only the mark itself but also the whole histone and even the histone-DNA complex called a nucleosome. In other words, recognising H3K79me2 by its “readers” may require a native nucleosome- or chromatin-context. Second, the interaction between the “readers” and H3K79me2 can be weak or even transient and thereby easily lost during the “fishing” process. ‘To capture H3K79me2 “readers”, we must upgrade our “bait” and “hook”,’ says Li. But it was not trivial. Li's lab spent more than five years developing their new tool. Instead of using a small fragment of the histone protein, they chemically synthesised an intact nucleosome with an upgraded tri-functional “hook” and H3K79me2 as the “bait” (Figure 2). Using this new technology, the team successfully identified a protein called menin as the “reader” of H3K79me2. To understand how menin “reads” the H3K79me2 mark, the team adopted a cutting-edge technology called cryo-electron microscopy to visualise the molecular details of this interaction. ‘Unravelling the details of how menin binds H3K79 methylation is key to designing new drugs to treat cancers associated with misregulated H3K79me2’, says Professor Li. The pioneering work by Li and co-workers have advanced our understanding of the fundamental biological processes of gene regulation. These findings also open new opportunities for developing novel therapeutic agents to treat human diseases caused by abnormal levels of H3K79 methylation. The journal paper can be accessed here.  Click here to learn more about the research group of Professor Xiang David Li.    Figure 2. The research team chemically synthesised an intact nucleosome with an upgraded tri-functional “hook” and H3K79me2 as the “bait”. Using this new technology, the team successfully identified a protein called menin as the “reader” of H3K79me2. Image credit: Xiang David Li Group – The Laboratory of Chemical Epigenetics. 

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Secretin is involved in the activation of the subfornical organ excitatory neurons under osmotic thirst and hypovolemic thirst.                 Image credit: Dr Fengwei ZHANG

HKU neuroscientists discover a novel neural mechanisms of secretin receptor in regulating water intake, providing new ideas for solving hydromineral imbalance symptoms

Animals instinctively find and consume water when feeling thirsty in order to restore body fluid osmolality and plasma volume to their set points. The feeling of thirst is strongly influenced by the subfornical organ (SFO), a forebrain structure that integrates circulating signals, such as osmotic pressure and sodium contents, to stimulate thirst. While Secretin (SCT), a classical gastrointestinal hormone, has been implicated as a humoral factor regulating body-fluid homeostasis. As known that the mundane behavior of drinking water is actually governed by the complex neural mechanisms of SCT in the central nervous system, but how the signalling is involved in this process was unclear. Recently, a research team from the School of Biological Sciences (SBS) at The University of Hong Kong (HKU) collaborated with Jinan University and the Chinese University of Hong Kong (CUHK) to adopt a projection-specific gene deletion approach, demonstrating the neural mechanism for the first time, which reveals the important role of SCT Recepter (SCTR) in regulating drinking behaviour under thirst. This study not only expands the functional boundary of SCT, but also puts forward new insights into the regulation of the gut-brain axis in maintaining body fluid homeostasis, which provides new ideas for solving hydromineral imbalance symptoms (e.g., fatigue, headaches, arrhythmia, nausea, and vomiting etc.). Their findings have been published in the top journal Current Biology. The SFO located in the mammalian forebrain is the key site that regulates internal water balance, while SFO neurons are poised to receive signals about plasma osmolality, blood pressure, and hormones, which integrates these information to regulate thirst. Excitatory neurons in SFO are strongly activated under dehydration, and activation of such neurons can promote voracious water intake even under hydrated conditions. Previous studies focused on dissecting the neural circuits underlying thirst, but how peptide signalling is involved in this process still needs to be better understood. SCT was recently identified as a key factor that regulates body fluid homeostasis. Central and peripheral administration of SCT triggered water intake in rodents. Notably, the SCTR was also expressed in the SFO and is activated by SCT from blood circulation, suggesting that they may directly involve in body fluid balance dominated by SFO. To better understand the neural basis of how SCTR regulates thirst, the research team led by Professor Billy CHOW from HKU SBS, Dr Li ZHANG from Jinan University and Professor YUNG Wingho from CUHK jointly demonstrated that SCTR deletion in the SFO significantly reduces water intake in dehydrated mice. The team used electrophysiology and fibre photometry to show the SCT-SCTR axis participants in the activation of SFO excitatory neurons under dehydration. Moreover, they adopted a projection-specific gene deletion approach to demonstrate that SCTR participates in SFO to the median preoptic nucleus (MnPO) neurons pathway to regulate thirst. In short, this study reveals the important role of SCTR in regulating drinking behavior under thirst. SCTR may maintain normal drinking behaviour after thirst by regulating the membrane current changes of SFO excitatory neurons and mediating the neural excitability of the SFO to the MnPO pathway. This study provides a new perspective for understanding the role of gastrointestinal peptides in human body fluid homeostatic regulation. ‘Discovering the role of SCT in the central nervous system is exciting, but this is just the beginning, and our research is gradually expanding the role of SCT in the brain,’ says Professor Chow. ‘We will continue to follow the traces of SCT signals in the brain to descript a clearer neural mechanism.’ The journal paper can be accessed here. More information about Dr Billy Chow and his research group can be found from their group’s webpage. Professor Billy Chow (middle of the first row) and his research group.

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