Elevated NSD3 histone methylation activity drives squamous cell lung cancer

Amplification of chromosomal region 8p11-12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC)(1-3). The FGFR1 gene is the main candidate driver of tumorigenesis within this region(4). However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful(5). Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11-12 amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11-12 candidate LUSC drivers, increased expression of NSD3 correlated strongly with its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour growth and extended survival in a mouse model of LUSC. We identify an LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic analyses revealed that the T1232A substitution elicited localized mobility changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in vivo accelerated tumorigenesis and decreased overall survival in mouse models of LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the chromatin landscape to promote oncogenic gene expression signatures. Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted transformation in human tracheobronchial cells and growth of xenografted human LUSC cell lines with amplification of 8p11-12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplification or the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally, NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain inhibition. Thus, our work identifies NSD3 as a principal 8p11-12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Integration of science and coastal management: a case study of Hong Kong

Coastal management practices, regulatory decision-making, and land use planning activities along coastal areas have historically been made with insufficient scientific information concerning the dynamic environment. The idea of integration of science and coastal management has risen rapidly in both environmental science and public environmental policy since the mid-1990s, and encouraged innovative relationships between scientists and practitioners in a range of contexts. In this paper, based on materials analysis, we explore the existing practices, evaluating past successes and failures in the management mode of coastal areas in Hong Kong. Though this case study we examine the challenges Hong Kong faces presently, illustrate the strong need for integrating science and coastal management

Applying SWOT-AHP Analysis in Sustainable Marine Development Plan: Case Study in Shantou Municipality

Having understood the disadvantages of traditional marine development mode, the sustainable development mode, which makes overall planning of land and sea and endorses equal importance to both development and protection, is attracting more and more attentions from coastal regions. To formulate the right orientation of marine development, this thesis attempts to apply SWOT-AHP method, a combination of qualitative and quantitative analysis, into strategy formulation. And, by introducing revision coefficient, this thesis modifies the current quantitative calculation methods. Finally, a SWOT-AHP analysis system of sustainable marine development plan has been constructed. In the study of Shantou marine development, strength, weakness, opportunity and threat factors have been listed through symposium and data analysis; attribution and impacts of these factors are calculated from experts' evaluation. Based on these scores, a strategic quadrilateral is built, which could directly reflect the orientation of Shantou marine development. According to the analysis results, we can see that the advantage of Shantou marine development is obvious. Shantou should take growth strategy to make better use of its strength and opportunity factors; and transform its development mode from the traditional overexploitation to a sustainable one, which highly emphasizes on protecting marine ecological services and achieving the equilibrium of both ecological civilization and economic growth