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Author(s): Wanqiu Li [sup.1] , Wei Tian [sup.2] , Gang Yuan [sup.3] , Pujuan Deng [sup.2] , Deepanwita Sengupta [sup.3] , Zhongjun Cheng [sup.4] , Yinghua Cao [sup.2] , Jiahao [...], Histone methyltransferases of the nuclear receptor-binding SET domain protein (NSD) family, including NSD1, NSD2 and NSD3, have crucial roles in chromatin regulation and are implicated in oncogenesis.sup.1,2. NSD enzymes exhibit an autoinhibitory state that is relieved by binding to nucleosomes, enabling dimethylation of histone H3 at Lys36 (H3K36).sup.3-7. However, the molecular basis that underlies this mechanism is largely unknown. Here we solve the cryo-electron microscopy structures of NSD2 and NSD3 bound to mononucleosomes. We find that binding of NSD2 and NSD3 to mononucleosomes causes DNA near the linker region to unwrap, which facilitates insertion of the catalytic core between the histone octamer and the unwrapped segment of DNA. A network of DNA- and histone-specific contacts between NSD2 or NSD3 and the nucleosome precisely defines the position of the enzyme on the nucleosome, explaining the specificity of methylation to H3K36. Intermolecular contacts between NSD proteins and nucleosomes are altered by several recurrent cancer-associated mutations in NSD2 and NSD3. NSDs that contain these mutations are catalytically hyperactive in vitro and in cells, and their ectopic expression promotes the proliferation of cancer cells and the growth of xenograft tumours. Together, our research provides molecular insights into the nucleosome-based recognition and histone-modification mechanisms of NSD2 and NSD3, which could lead to strategies for therapeutic targeting of proteins of the NSD family. Cryo-electron microscopy structures of the nucleosome-bound NSD2 and NSD3 histone methyltransferases reveal the molecular basis of their histone modification activity, and show how mutations in these proteins can lead to oncogenesis.

The jumonji (JMJ) family of histone demethylases are Fe2+- and α-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance, as well as in development, physiology and disease. However, because of the absence of any selective inhibitors, the relevance of the demethylase activity of JMJ enzymes in regulating cellular responses remains poorly understood. Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX). The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. We exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily. We demonstrate that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Our results resolve the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provide encouragement for designing small-molecule inhibitors to allow selective pharmacological intervention across the JMJ family.

Switchable adhesion, especially that responds to both solids and liquids simultaneously, has recently attracted much attention due to its wide applications. However, it is hard to endow a surface with switchable solid/liquid adhesion and high maximum solid adhesion at the same time due to the opposing requirement of solid contact fraction. In this paper, a shape memory/elasticity dual‐structure adjustable strategy to satisfy that special demand is offered. In detail, by constructing the shape memory epoxy resin arrays with spherical polyurethane mushroom on Fe3O4 doped substrate, a smart photo/thermal responsive material with switchable solid/liquid adhesion is prepared. In the work, the structure of the shape memory resin arrays can be reversibly changed between upright and collapsed states, leading to switchable solid and liquid adhesion. Meantime, the structure of the polyurethane mushroom can be squeezed to increase the contact area with the solid and spontaneously recovered, which can effectively improve the maximum solid adhesion with no effect on liquid adhesion. Furthermore, the obtained material has good cyclicity and universality, which has been applied to selectively pick silicon wafers and water droplets. The findings of this study may provide new strategies for the development of smart adhesive materials. [ABSTRACT FROM AUTHOR]

The phenomenon of controlled droplet transport has promising application prospects in various fields. Active droplet transport mode is controllable through continuous external stimuli. By contrast, self‐transport is a more environmentally friendly and energy‐efficient passive transport mode but lacks controllability. In this study, controlled self‐transport is achieved by constructing a shape memory polymer (SMP) tube with a lubricated magnetic‐responsive gel inner surface. The asymmetrical shape of the tube, combined with the lubricated inner surface, enables directional self‐transport of droplets without external stimuli. Furthermore, the resistance on the inner gel surface can be altered by regulating the magnetic field to achieve effective active control during the self‐transport process. Thus, smart in situ control of droplet transport can be achieved by integrating the macroscale shape variation of the tube with the dynamic control of the inner surface microstructure. Owing to the fast magnetic responsivity and in situ controllability of the self‐transport process, the SMP lubricated tube demonstrates the ability to transport a variety of liquids and can be designed as a micro‐reactor for step‐by‐step droplet detection. The findings of this study may provide guidance for the development of intelligent interface materials and microfluidic devices. [ABSTRACT FROM AUTHOR]