macroH2A2 antagonizes epigenetic programs of stemness in glioblastoma.

Self-renewal is a crucial property of glioblastoma cells that is enabled by the choreographed functions of chromatin regulators and transcription factors. Identifying targetable epigenetic mechanisms of self-renewal could therefore represent an important step toward developing effective treatments for this universally lethal cancer. Here we uncover an epigenetic axis of self-renewal mediated by the histone variant macroH2A2. With omics and functional assays deploying patient-derived in vitro and in vivo models, we show that macroH2A2 shapes chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal. macroH2A2 also sensitizes cells to small molecule-mediated cell death via activation of a viral mimicry response. Consistent with these results, our analyses of clinical cohorts indicate that high transcriptional levels of this histone variant are associated with better prognosis of high-grade glioma patients. Our results reveal a targetable epigenetic mechanism of self-renewal controlled by macroH2A2 and suggest additional treatment approaches for glioblastoma patients.

Hundred million years of landscape dynamics from catchment to global scale.

Our capability to reconstruct past landscapes and the processes that shape them underpins our understanding of paleo-Earth. We take advantage of a global-scale landscape evolution model assimilating paleoelevation and paleoclimate reconstructions over the past 100 million years. This model provides continuous quantifications of metrics critical to the understanding of the Earth system, from global physiography to sediment flux and stratigraphic architectures. We reappraise the role played by surface processes in controlling sediment delivery to the oceans and find stable sedimentation rates throughout the Cenozoic with distinct phases of sediment transfer from terrestrial to marine basins. Our simulation provides a tool for identifying inconsistencies in previous interpretations of the geological record as preserved in sedimentary strata, and in available paleoelevation and paleoclimatic reconstructions.

Javanese Homo erectus on the move in SE Asia circa 1.8 Ma.

The migration of Homo erectus in Southeast Asia during Early Pleistocene is cardinal to our comprehension of the evolution of the genus Homo. However, the limited consideration of the rapidly changing physical environment, together with controversial datings of hominin bearing sites, make it challenging to secure the robust timeline needed to unveil the behavior of early humans. Here, we reappraise the first appearance datum of Javanese H. erectus by adding the most reliable age constraints based on cosmogenic nuclides [Formula: see text]Be and [Formula: see text]Al produced in situ to a compilation of earlier estimates. We find that H. erectus reached Java and dwelled at Sangiran, Java, ca. 1.8 Ma. Using this age as a baseline, we develop a probabilistic approach to reconstruct their dispersal routes, coupling ecological movement simulations to landscape evolution models forced by reconstructed geodynamic and climatic histories. We demonstrate that the hospitable terra firma conditions of Sundaland facilitated the prior dispersal of hominins to the edge of Java, where they conversely could not settle until the Javanese archipelago emerged from the sea and connected to Sundaland. The dispersal of H. erectus across Sundaland occurred over at least tens to hundreds kyr, a time scale over which changes in their physical environment, whether climatic or physiographic, may have become primary forcings on their behavior. Our comprehensive reconstruction method to unravel the peopling timeline of SE Asia provides a novel framework to evaluate the evolution of early humans.

Hi-C detects genomic structural variants in peripheral blood of pediatric leukemia patients.

B-cell acute lymphoblastic leukemia (B-ALL) is often driven by chromosome translocations that result in recurrent and well-studied gene fusions. Currently, fluorescent in situ hybridization probes are used to detect candidate translocations in bone marrow samples from B-ALL patients. Recently Hi-C, a sequencing-based technique originally designed to reconstruct the three-dimensional architecture of the nuclear genome, was shown to effectively recognize structural variants. Here, we demonstrate that Hi-C can be used as a genome-wide assay to detect translocations and other structural variants of potential clinical interest. Structural variants were identified in both bone marrow and peripheral blood samples, including an ETV6-RUNX1 translocation present in one pediatric B-ALL patient. Our report provides proof of principle that Hi-C could be an effective strategy to globally detect driver structural variants in B-ALL peripheral blood specimens, reducing the need for invasive bone marrow biopsies and candidate-based clinical tests.

Subduction controls the distribution and fragmentation of Earth's tectonic plates.

The theory of plate tectonics describes how the surface of Earth is split into an organized jigsaw of seven large plates of similar sizes and a population of smaller plates whose areas follow a fractal distribution. The reconstruction of global tectonics during the past 200 million years suggests that this layout is probably a long-term feature of Earth, but the forces governing it are unknown. Previous studies, primarily based on the statistical properties of plate distributions, were unable to resolve how the size of the plates is determined by the properties of the lithosphere and the underlying mantle convection. Here we demonstrate that the plate layout of Earth is produced by a dynamic feedback between mantle convection and the strength of the lithosphere. Using three-dimensional spherical models of mantle convection that self-consistently produce the plate size­frequency distribution observed for Earth, we show that subduction geometry drives the tectonic fragmentation that generates plates. The spacing between the slabs controls the layout of large plates, and the stresses caused by the bending of trenches break plates into smaller fragments. Our results explain why the fast evolution in small back-arc plates reflects the marked changes in plate motions during times of major reorganizations. Our study opens the way to using convection simulations with plate-like behaviour to unravel how global tectonics and mantle convection are dynamically connected.