Volume 553 Number 7689

Editorials

News

News Features

News & Views

Trapped particle makes 3D images p.408

A technique in which a small particle is trapped and moved by laser light has been used to produce visual representations of objects in three dimensions, offering key advantages over currently used approaches.

doi: 10.1038/d41586-018-00859-z

Ageing-related receptors resolved p.409

Ageing is a regulated process in which hormones have pivotal roles. Crystal structures of two hormone co-receptors should be informative for drug discovery focused on age-related disorders.

doi: 10.1038/d41586-017-09032-4

A beacon at the dawn of the Universe p.410

Quasars are the brightest continuously emitting sources of radiation in the Universe. Measurements of the most distant quasar ever detected reveal details about the evolution and structure of the early Universe.

doi: 10.1038/d41586-018-00818-8

Satellite images show China going green p.411

Large-scale tree-planting projects have taken place in regions of China prone to soil erosion. Satellite imagery reveals the effects of this work, and shows that a predicted vegetation decline didn’t occur during a period of drought.

doi: 10.1038/d41586-018-00996-5

Eighty years of superfluidity p.413

In 1938, two studies demonstrated that liquid helium-4 flows without friction or viscosity at temperatures close to absolute zero. The finding led to major advances in our understanding of low-temperature physics.

doi: 10.1038/d41586-018-00417-7

Kiss-and-tell way to track cell contacts p.414

Transient cellular contacts are essential for the generation of an immune response, but these are difficult to measure in vivo. A labelling technique now offers a way to record such interactions between cells.

doi: 10.1038/d41586-018-00488-6

Articles

Letters

A photophoretic-trap volumetric display p.486

Photophoretic optical trapping of cellulose particles and persistence of vision are used to produce real-space volumetric images that can be viewed from all angles, in geometries unachievable by holograms and light-field technologies.

doi: 10.1038/nature25176

Monitoring T cell–dendritic cell interactions in vivo by intercellular enzymatic labelling p.496

Interactions between different cell types are essential for multiple biological processes, including immunity, embryonic development and neuronal signalling. Although the dynamics of cell–cell interactions can be monitored in vivo by intravital microscopy, this approach does not provide any information on the receptors and ligands involved or enable the isolation of interacting cells for downstream analysis. Here we describe a complementary approach that uses bacterial sortase A-mediated cell labelling across synapses of immune cells to identify receptor–ligand interactions between cells in living mice, by generating a signal that can subsequently be detected ex vivo by flow cytometry. We call this approach for the labelling of ‘kiss-and-run’ interactions between immune cells ‘Labelling Immune Partnerships by SorTagging Intercellular Contacts’ (LIPSTIC). Using LIPSTIC, we show that interactions between dendritic cells and CD4+ T cells during T-cell priming in vivo occur in two distinct modalities: an early, cognate stage, during which CD40–CD40L interactions occur specifically between T cells and antigen-loaded dendritic cells; and a later, non-cognate stage during which these interactions no longer require prior engagement of the T-cell receptor. Therefore, LIPSTIC enables the direct measurement of dynamic cell–cell interactions both in vitro and in vivo. Given its flexibility for use with different receptor–ligand pairs and a range of detectable labels, we expect that this approach will be of use to any field of biology requiring quantification of intercellular communication.

doi: 10.1038/nature25442

Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling p.501

Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains. Here we describe the crystal structures of free and ligand-bound β-klotho extracellular regions that reveal the molecular mechanism that underlies the specificity of FGF21 towards β-klotho and demonstrate how the FGFR is activated in a klotho-dependent manner. β-Klotho serves as a primary ‘zip code’-like receptor that acts as a targeting signal for FGF21, and FGFR functions as a catalytic subunit that mediates intracellular signalling. Our structures also show how the sugar-cutting enzyme glycosidase has evolved to become a specific receptor for hormones that regulate metabolic processes, including the lowering of blood sugar levels. Finally, we describe an agonistic variant of FGF21 with enhanced biological activity and present structural insights into the potential development of therapeutic agents for diseases linked to endocrine FGFs.

doi: 10.1038/nature25010

Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia p.511

Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5′-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5′-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.

doi: 10.1038/nature25186

A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies p.515

The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies. Here we show that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that has previously been labelled as a ‘super-enhancer’ is essential for the regulation of Myc expression levels in both normal haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in haematopoietic stem cells and progenitors. This caused an accumulation of differentiation-arrested multipotent progenitors and loss of myeloid and B cells, mimicking the phenotype caused by Mx1-Cre-mediated conditional deletion of the Myc gene in haematopoietic stem cells. This super-enhancer comprises multiple enhancer modules with selective activity that recruits a compendium of transcription factors, including GFI1b, RUNX1 and MYB. Analysis of mice carrying deletions of individual enhancer modules suggests that specific Myc expression levels throughout most of the haematopoietic hierarchy are controlled by the combinatorial and additive activity of individual enhancer modules, which collectively function as a ‘blood enhancer cluster’ (BENC). We show that BENC is also essential for the maintenance of MLL–AF9-driven leukaemia in mice. Furthermore, a BENC module, which controls Myc expression in mouse haematopoietic stem cells and progenitors, shows increased chromatin accessibility in human acute myeloid leukaemia stem cells compared to blasts. This difference correlates with MYC expression and patient outcome. We propose that clusters of enhancers, such as BENC, form highly combinatorial systems that allow precise control of gene expression across normal cellular hierarchies and which also can be hijacked in malignancies.

doi: 10.1038/nature25193