H3F3A K27M Mutations Drives a Repressive Transcriptome by Modulating Chromatin Accessibility, Independent of H3K27me3 in Diffuse Midline Glioma.

Background: Heterozygous histone H3.3K27M mutation is a primary oncogenic driver of Diffuse Midline Glioma (DMG). H3.3K27M inhibits the Polycomb Repressive Complex 2 (PRC2) methyltransferase complex, leading to a global reduction and redistributing of the repressive H3 lysine 27 tri-methylation. This rewiring of the epigenome is thought to promote gliomagenesis. Methods: We established novel, isogenic DMG patient-derived cell lines that have been CRISPR-Cas9 edited to H3.3 WT or H3.3K27M alone and in combination with EZH2 and EZH1 co-deletion, inactivating PRC2 methyltransferase activity of PRC2 and eliminating H3K27me3. Results: RNA-seq and ATAC-seq analysis of these cells revealed that K27M has a novel epigenetic effect that appears entirely independent of its effects on PRC2 function. While the loss of the PRC2 complex led to a systemic induction of gene expression (including HOX gene clusters) and upregulation of biological pathways, K27M led to a balanced gene deregulation but having an overall repressive effect on the biological pathways. Importantly, the genes uniquely deregulated by the K27M mutation, independent of methylation loss, are closely associated with changes in chromatin accessibility, with upregulated genes becoming more accessible. Notably, the PRC2- independent function of K27M appears necessary for tumorigenesis as xenografts of our H3.3K27M/EZH1/2 WT cells developed into tumors, while H3.3/EZH1/2 KO cells did not. Conclusion: We demonstrate that K27M mutation alters chromatin accessibility and uniquely deregulates genes, independent of K27 methylation. We further show the mutation's role in altering biological pathways and its necessity for tumor development. Key Points: We revealed genes regulated by H3.3K27M mutation and PRC2 in DMG.H3.3K27M mutation alters chromosome accessibility independent of H3K27me3.PRC2-independent effects of K27M mutation are crucial for tumor development. Importance of the Study: This study is the first to demonstrate that H3F3A K27M mutations drive a repressive transcriptome by modulating chromatin accessibility independently of H3K27 trimethylation in Diffuse Midline Glioma (DMG). By isolating the effects of H3.3 K27me3 loss from those of the K27M mutation, we identified common and unique genes and pathways affected by each. We found that genes uniquely deregulated by K27M showed increased chromatin accessibility and upregulated gene expression, unlike other gene subsets affected by PRC2 knockout. Importantly, we determined the PRC2-independent function of K27M is also essential for tumorigenesis, as xenografts of H3.3 K27M/PRC2 WT cell lines formed tumors, while H3.3WT/PRC2 WT and K27M/PRC2 knockout cells did not. This research builds upon and advances prior studies, such as those identifying EZH2 as a therapeutic target in H3.3K27M DMGs, by revealing critical new pathways for gliomagenesis. The translational significance lies in identifying novel therapeutic targets against this aggressive pediatric cancer.

Wild fish consumption can balance nutrient retention in farmed fish.

Wild fish used as aquafeeds could be redirected towards human consumption to support sustainable marine resource use. Here we use mass-balance fish-in/fish-out ratio approaches to assess nutrient retention in salmon farming and identify scenarios that provide more nutrient-rich food to people. Using data on Norway's salmon farms, our study revealed that six of nine dietary nutrients had higher yields in wild fish used for feeds, such as anchovies and mackerel, than in farmed salmon production. Reallocating one-third of food-grade wild feed fish towards direct human consumption would increase seafood production, while also retaining by-products for use as aquafeeds, thus maximizing nutrient utilization of marine resources.

Quantifying energy and nutrient fluxes in coral reef food webs.

The movement of energy and nutrients through ecological communities represents the biological 'pulse' underpinning ecosystem functioning and services. However, energy and nutrient fluxes are inherently difficult to observe, particularly in high-diversity systems such as coral reefs. We review advances in the quantification of fluxes in coral reef fishes, focusing on four key frameworks: demographic modelling, bioenergetics, micronutrients, and compound-specific stable isotope analysis (CSIA). Each framework can be integrated with underwater surveys, enabling researchers to scale organismal processes to ecosystem properties. This has revealed how small fish support biomass turnover, pelagic subsidies sustain fisheries, and fisheries benefit human health. Combining frameworks, closing data gaps, and expansion to other aquatic ecosystems can advance understanding of how fishes contribute to ecosystem functions and services.

Climate change exacerbates nutrient disparities from seafood.

Seafood is an important source of bioavailable micronutrients supporting human health, yet it is unclear how micronutrient production has changed in the past or how climate change will influence its availability. Here combining reconstructed fisheries databases and predictive models, we assess nutrient availability from fisheries and mariculture in the past and project their futures under climate change. Since the 1990s, availabilities of iron, calcium and omega-3 from seafood for direct human consumption have increased but stagnated for protein. Under climate change, nutrient availability is projected to decrease disproportionately in tropical low-income countries that are already highly dependent on seafood-derived nutrients. At 4 oC of warming, nutrient availability is projected to decline by ~30% by 2100 in low income countries, while at 1.5-2.0 oC warming, decreases are projected to be ~10%. We demonstrate the importance of effective mitigation to support nutritional security of vulnerable nations and global health equity.

Trophic distribution of nutrient production in coral reef fisheries.

Coral reef fisheries supply nutritious catch to tropical coastal communities, where the quality of reef seafood is determined by both the rate of biomass production and nutritional value of reef fishes. Yet our understanding of reef fisheries typically uses targets of total reef fish biomass rather than individual growth (i.e. biomass production) and nutrient content (i.e. nutritional value of reef fish), limiting the ability of management to sustain the productivity of nutritious catches. Here, we use modelled growth coefficients and nutrient concentrations to develop a new metric of nutrient productivity of coral reef fishes. We then evaluate this metric with underwater visual surveys of reef fish assemblages from four tropical countries to examine nutrient productivity of reef fish food webs. Species' growth coefficients were associated with nutrients that vary with body size (calcium, iron, selenium and zinc), but not total nutrient density. When integrated with fish abundance data, we find that herbivorous species typically dominate standing biomass, biomass turnover and nutrient production on coral reefs. Such bottom-heavy trophic distributions of nutrients were consistent across gradients of fishing pressure and benthic composition. We conclude that management restrictions that promote sustainability of herbivores and other low trophic-level species can sustain biomass and nutrient production from reef fisheries that is critical to the food security of over 500 million people in the tropics.

H3K27me3 in Diffuse Midline Glioma and Epithelial Ovarian Cancer: Opposing Epigenetic Changes Leading to the Same Poor Outcomes.

Histone post-translational modifications modulate gene expression through epigenetic gene regulation. The core histone H3 family members, H3.1, H3.2, and H3.3, play a central role in epigenetics. H3 histones can acquire many post-translational modifications, including the trimethylation of H3K27 (H3K27me3), which represses transcription. Triple methylation of H3K27 is performed by the histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2), a component of the Polycomb Repressive Complex 2. Both global increases and decreases in H3K27me3 have been implicated in a wide range of cancer types. Here, we explore how opposing changes in H3K27me3 contribute to cancer by highlighting its role in two vastly different cancer types; (1) a form of glioma known as diffuse midline glioma H3K27-altered and (2) epithelial ovarian cancer. These two cancers vary widely in the age of onset, sex, associated mutations, and cell and organ type. However, both diffuse midline glioma and ovarian cancer have dysregulation of H3K27 methylation, triggering changes to the cancer cell transcriptome. In diffuse midline glioma, the loss of H3K27 methylation is a primary driving factor in tumorigenesis that promotes glial cell stemness and silences tumor suppressor genes. Conversely, hypermethylation of H3K27 occurs in late-stage epithelial ovarian cancer, which promotes tumor vascularization and tumor cell migration. By using each cancer type as a case study, this review emphasizes the importance of H3K27me3 in cancer while demonstrating that the mechanisms of histone H3 modification and subsequent gene expression changes are not a one-size-fits-all across cancer types.

Safeguarding nutrients from coral reefs under climate change.

The sustainability of coral reef fisheries is jeopardized by complex and interacting socio-ecological stressors that undermine their contribution to food and nutrition security. Climate change has emerged as one of the key stressors threatening coral reefs and their fish-associated services. How fish nutrient concentrations respond to warming oceans remains unclear but these responses are probably affected by both direct (metabolism and trophodynamics) and indirect (habitat and species range shifts) effects. Climate-driven coral habitat loss can cause changes in fish abundance and biomass, revealing potential winners and losers among major fisheries targets that can be predicted using ecological indicators and biological traits. A critical next step is to extend research focused on the quantity of available food (fish biomass) to also consider its nutritional quality, which is relevant to progress in the fields of food security and malnutrition. Biological traits are robust predictors of fish nutrient content and thus potentially indicate how climate-driven changes are expected to impact nutrient availability within future food webs on coral reefs. Here, we outline future research priorities and an anticipatory framework towards sustainable reef fisheries contributing to nutrition-sensitive food systems in a warming ocean.

Managing fisheries for maximum nutrient yield.

Wild-caught fish are a bioavailable source of nutritious food that, if managed strategically, could enhance diet quality for billions of people. However, optimising nutrient production from the sea has not been a priority, hindering development of nutrition-sensitive policies. With fisheries management increasingly effective at rebuilding stocks and regulating sustainable fishing, we can now begin to integrate nutritional outcomes within existing management frameworks. Here, we develop a conceptual foundation for managing fisheries for multispecies Maximum Nutrient Yield (mMNY). We empirically test our approach using size-based models of North Sea and Baltic Sea fisheries and show that mMNY is predicted by the relative contribution of nutritious species to total catch and their vulnerability to fishing, leading to trade-offs between catch and specific nutrients. Simulated nutrient yield curves suggest that vitamin D, which is deficient in Northern European diets, was underfished at fishing levels that returned maximum catch weights. Analysis of global catch data shows there is scope for nutrient yields from most of the world's marine fisheries to be enhanced through nutrient-sensitive fisheries management. With nutrient composition data now widely available, we expect our mMNY framework to motivate development of nutrient-based reference points in specific contexts, such as data-limited fisheries. Managing for mMNY alongside policies that promote access to fish could help close nutrient gaps for coastal populations, maximising the contribution of wild-caught fish to global food and nutrition security.

Reef fishes weaken dietary preferences after coral mortality, altering resource overlap.

The direct and indirect effects of climate change can affect, and are mediated by, changes in animal behaviour. However, we often lack sufficient empirical data to assess how large-scale disturbances affect the behaviour of individuals, which scales up to influence communities. Here, we investigate these patterns by focusing on the foraging behaviour of butterflyfishes, prominent coral-feeding fishes on coral reefs, before and after a mass coral bleaching event in Iriomote, Japan. In response to 65% coral mortality, coral-feeding fishes broadened their diets, showing a significant weakening of dietary preferences across species. Multiple species reduced their consumption of bleaching-sensitive Acropora corals, while expanding their diets to consume a variety of other coral genera. This resulted in decreased dietary overlap among butterflyfishes. Behavioural changes in response to bleaching may increase resilience of coral reef fishes in the short term. However, coral mortality has reduced populations of coral-feeders world-wide, indicating the changes in feeding behaviour we document here may not be sufficient to ensure long-term resilience of butterflyfishes on coral reefs.

Climate-induced increases in micronutrient availability for coral reef fisheries.

Climate change is transforming coral reefs, threatening supply of essential dietary micronutrients from small-scale fisheries to tropical coastal communities. Yet the nutritional value of reef fisheries and climate impacts on micronutrient availability remain unclear, hindering efforts to sustain food and nutrition security. Here, we measure nutrient content in coral reef fishes in Seychelles and show that reef fish are important sources of selenium and zinc and contain levels of calcium, iron, and omega-3 fatty acids comparable with other animal-source foods. Using experimental fishing, we demonstrate that iron and zinc are enriched in fishes caught on regime-shifted macroalgal habitats, whereas selenium and omega-3 varied among species. We find substantial increases in nutrients available to fisheries over two decades following coral bleaching, particularly for iron and zinc after macroalgal regime shifts. Our findings indicate that, if managed sustainably, coral reef fisheries could remain important micronutrient sources along tropical coastlines despite escalating climate impacts.

Small pelagic fish supply abundant and affordable micronutrients to low- and middle-income countries.

Wild-caught fish provide an irreplaceable source of essential nutrients in food-insecure places. Fishers catch thousands of species, yet the diversity of aquatic foods is often categorized homogeneously as 'fish', obscuring an understanding of which species supply affordable, nutritious and abundant food. Here, we use catch, economic and nutrient data on 2,348 species to identify the most affordable and nutritious fish in 39 low- and middle-income countries. We find that a 100 g portion of fish cost between 10 and 30% of the cheapest daily diet, with small pelagic fish (herring, sardine, anchovy) being the cheapest nutritious fish in 72% of countries. In sub-Saharan Africa, where nutrient deficiencies are rising, <20% of small pelagic catch would meet recommended dietary fish intakes for all children (6 months to 4 years old) living near to water bodies. Nutrition-sensitive policies that ensure local supplies and promote consumption of wild-caught fish could help address nutrient deficiencies in vulnerable populations.

Microbial Shift in the Enteric Bacteriome of Coral Reef Fish Following Climate-Driven Regime Shifts.

Replacement of coral by macroalgae in post-disturbance reefs, also called a "coral-macroalgal regime shift", is increasing in response to climate-driven ocean warming. Such ecosystem change is known to impact planktonic and benthic reef microbial communities but few studies have examined the effect on animal microbiota. In order to understand the consequence of coral-macroalgal shifts on the coral reef fish enteric bacteriome, we used a metabarcoding approach to examine the gut bacteriomes of 99 individual fish representing 36 species collected on reefs of the Inner Seychelles islands that, following bleaching, had either recovered to coral domination, or shifted to macroalgae. While the coral-macroalgal shift did not influence the diversity, richness or variability of fish gut bacteriomes, we observed a significant effect on the composition (R2 = 0.02; p = 0.001), especially in herbivorous fishes (R2 = 0.07; p = 0.001). This change is accompanied by a significant increase in the proportion of fermentative bacteria (Rikenella, Akkermensia, Desulfovibrio, Brachyspira) and associated metabolisms (carbohydrates metabolism, DNA replication, and nitrogen metabolism) in relation to the strong turnover of Scarinae and Siganidae fishes. Predominance of fermentative metabolisms in fish found on macroalgal dominated reefs indicates that regime shifts not only affect the taxonomic composition of fish bacteriomes, but also have the potential to affect ecosystem functioning through microbial functions.

Micronutrient supply from global marine fisheries under climate change and overfishing.

Fish are rich in bioavailable micronutrients, such as zinc and iron, deficiencies of which are a global food security concern.1,2 Global marine fisheries yields are threatened by climate change and overfishing,3,4 yet understanding of how these stressors affect the nutrients available from fisheries is lacking.5,6 Here, using global assessments of micronutrient content2 and fisheries catch data,7 we investigate how the vulnerability status of marine fish species8,9 may translate into vulnerability of micronutrient availability at scales of both individual species and entire fishery assemblages for 157 countries. We further quantify the micronutrient evenness of catches to identify countries where interventions can optimize micronutrient supply. Our global analysis, including >800 marine fish species, reveals that, at a species level, micronutrient availability and vulnerability to both climate change and overfishing varies greatly, with tropical species displaying a positive co-tolerance, indicating greater persistence to both stressors at a community level.10 Global fisheries catches had relatively low nutritional vulnerability to fishing. Catches with higher species richness tend to be nutrient dense and evenly distributed but are more vulnerable to climate change, with 40% of countries displaying high vulnerability. Countries with high prevalence of inadequate micronutrient intake tend to have the most nutrient-dense catches, but these same fisheries are highly vulnerable to climate change, with relatively lower capacity to adapt.11 Our analysis highlights the need to consolidate fisheries, climate, and food policies to secure the sustainable contribution of fish-derived micronutrients to food and nutrition security.

Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations.

Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

BRAF inhibition in melanoma is associated with the dysregulation of histone methylation and histone methyltransferases.

The development of mutant BRAF inhibitors has improved the outcome for melanoma patients with BRAFV600E mutations. Although the initial response to these inhibitors can be dramatic, sometimes resulting in complete tumor regression, the majority of melanomas become resistant. To study resistance to BRAF inhibition, we developed a novel mouse model of melanoma using a tetracycline/doxycycline-regulated system that permits control of mutant BRAF expression. Treatment with doxycycline leads to loss of mutant BRAF expression and tumor regression, but tumors recur after a prolonged period of response to treatment. Vemurafenib, encorafenib and dabrafenib induce cell cycle arrest and apoptosis in BRAF melanoma cell lines; however, a residual population of tumor cells survive. Comparing gene expression in human cell lines and mouse tumors can assist with the identification of novel mechanisms of resistance. Accordingly, we conducted RNA sequencing analysis and immunoblotting on untreated and doxycycline-treated dormant mouse melanomas and human mutant BRAF melanoma cell lines treated with 2 µM vemurafenib for 20  days. We found conserved expression changes in histone methyltransferase genes ASH2, EZH2, PRMT5, SUV39H1, SUV39H2, and SYMD2 in P-ERK low, p-38 high melanoma cells following prolonged BRAF inhibition. Quantitative mass spectrometry, determined a corresponding reduction in histone Lys9 and Lys27 methylation and increase in Lys36 methylation in melanoma cell lines treated with 2 µM vemurafenib for 20  days. Thus, these changes as are part of the initiate response to BRAF inhibition and likely contribute to the survival of melanoma cells.

Changing role of coral reef marine reserves in a warming climate.

Coral reef ecosystems are among the first to fundamentally change in structure due to climate change, which leads to questioning of whether decades of knowledge regarding reef management is still applicable. Here we assess ecological responses to no-take marine reserves over two decades, spanning a major climate-driven coral bleaching event. Pre-bleaching reserve responses were consistent with a large literature, with higher coral cover, more species of fish, and greater fish biomass, particularly of upper trophic levels. However, in the 16 years following coral mortality, reserve effects were absent for the reef benthos, and greatly diminished for fish species richness. Positive fish biomass effects persisted, but the groups of fish benefiting from marine reserves profoundly changed, with low trophic level herbivores dominating the responses. These findings highlight that while marine reserves still have important roles on coral reefs in the face of climate change, the species and functional groups they benefit will be substantially altered.

Diversification insulates fisher catch and revenue in heavily exploited tropical fisheries.

Declines in commercial landings and increases in fishing fleet power have raised concerns over the continued provisioning of nutritional and economic services by tropical wild fisheries. Yet, because tropical fisheries are often data-poor, mechanisms that might buffer fishers to declines are not understood. This data scarcity undermines fisheries management, making tropical fishing livelihoods particularly vulnerable to changes in marine resources. We use high-resolution fisheries data from Seychelles to understand how fishing strategy (catch diversification) influences catch rates and revenues of individual fishing vessels. We show that average catch weight decreased by 65% over 27 years, with declines in all nine species groups coinciding with increases in fishing effort. However, for individual vessels, catch diversity was associated with larger catches and higher fishing revenues and with slower catch declines from 1990 to 2016. Management strategies should maximize catch diversity in data-poor tropical fisheries to help secure nutritional security while protecting fishing livelihoods.

Climatic and local stressor interactions threaten tropical forests and coral reefs.

Tropical forests and coral reefs host a disproportionately large share of global biodiversity and provide ecosystem functions and services used by millions of people. Yet, ongoing climate change is leading to an increase in frequency and magnitude of extreme climatic events in the tropics, which, in combination with other local human disturbances, is leading to unprecedented negative ecological consequences for tropical forests and coral reefs. Here, we provide an overview of how and where climate extremes are affecting the most biodiverse ecosystems on Earth and summarize how interactions between global, regional and local stressors are affecting tropical forest and coral reef systems through impacts on biodiversity and ecosystem resilience. We also discuss some key challenges and opportunities to promote mitigation and adaptation to a changing climate at local and global scales. This article is part of the theme issue 'Climate change and ecosystems: threats, opportunities and solutions'.

Thermal stress induces persistently altered coral reef fish assemblages.

Ecological communities are reorganizing in response to warming temperatures. For continuous ocean habitats this reorganization is characterized by large-scale species redistribution, but for tropical discontinuous habitats such as coral reefs, spatial isolation coupled with strong habitat dependence of fish species imply that turnover and local extinctions are more significant mechanisms. In these systems, transient marine heatwaves are causing coral bleaching and profoundly altering habitat structure, yet despite severe bleaching events becoming more frequent and projections indicating annual severe bleaching by the 2050s at most reefs, long-term effects on the diversity and structure of fish assemblages remain unclear. Using a 23-year time series spanning a thermal stress event, we describe and model structural changes and recovery trajectories of fish communities after mass bleaching. Communities changed fundamentally, with the new emergent communities dominated by herbivores and persisting for >15 years, a period exceeding realized and projected intervals between thermal stress events on coral reefs. Reefs which shifted to macroalgal states had the lowest species richness and highest compositional dissimilarity, whereas reefs where live coral recovered exceeded prebleaching fish richness, but remained dissimilar to prebleaching compositions. Given realized and projected frequencies of bleaching events, our results show that fish communities historically associated with coral reefs will not re-establish, requiring substantial adaptation by managers and resource users.

Publisher Correction: Productive instability of coral reef fisheries after climate-driven regime shifts.

In the version of this Article originally published, a technical error meant two proof corrections were not actioned. In the sentence that started "Fishery changes were underpinned…", a citation to ref. 9 was missing, and that to ref. 22 was misplaced. The sentence should have read: "Fishery changes were underpinned by species' differential responses to the post-bleaching benthic trajectories, suggesting that projections for reef fisheries that are based on habitat-driven loss of fish biomass (for example ref. 9) have overlooked the potential for increased productivity of low trophic levels22, particularly browsing herbivores on regime-shifted reefs." These errors have now been corrected in the Article.