Studies of the epigenomic signatures of many healthy and diseased human tissues could provide crucial infomation to link genetic variation and disease.
Science will benefit most from a combination of youthful innovation and hard-won experience.
Facility will study biomedical uses at attosecond resolution.
Researchers aim to cut passwords and people out of the data-safety equation.
Analysis of millions of papers finds that junior biomedical researchers tend to work on more innovative topics than their senior colleagues do.
Eurasian region gains ground as birthplace of Indo-European tongues.
Projects aim to mimic human body using networks of simulated organs.
Federal start-up funds inspire investment in ARPA-E technologies.
The idea of two sexes is simplistic. Biologists now think there is a wider spectrum than that.
The billions of specimens in natural-history museums are becoming more useful for tracking Earth's shrinking biodiversity. But the collections also face grave threats.
News & Views
Neurons in the brain's visual cortex receive inputs from thousands of other neurons. But it now emerges that each is strongly connected to only a few others: those most similar to itself. See Letter p.399
The contribution of explosions known as novae to the lithium content of the Milky Way is uncertain. Radioactive beryllium, which transforms into lithium, has been detected for the first time in one such explosion. See Letter p.381
The most powerful oxidant found in nature is compound Q, an enzymatic intermediate that oxidizes methane. New spectroscopic data have resolved the long-running controversy about Q's chemical structure. See Letter p.431
An ensemble of climate models predicts that winds along the world's coasts will intensify because of global warming, inducing more ocean upwelling — a process that will affect the health of coastal marine ecosystems. See Letter p.390
A package of papers investigates the functional regulatory elements in genomes that have been obtained from human tissue samples and cell lines. The implications of the project are presented here from three viewpoints. See Articles p.317, p.331, p.337 & p.344 and Letters p.350, p.355, p.360 & p.365
This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.
An analysis of genome-wide chromatin interactions during human embryonic stem cell differentiation reveals changes in chromatic organization and simultaneously identifies allele-resolved chromatin structure and differences in gene expression during differentiation.
Genome-wide association studies combined with data from epigenomic maps for immune cells have been used to fine-map causal variants for 21 autoimmune diseases; disease risk tends to be linked to single nucleotide polymorphisms in cell-type-specific enhancers, often in regions adjacent to transcription factor binding motifs.
Lineage-specific transcription factors and signalling pathways cooperate with pluripotency regulators to control the transcriptional networks that drive cell specification and exit from an embryonic stem cell state; here, we report genome-wide binding data for 38 transcription factors combined with analysis of epigenomic and gene expression data during the differentiation of human embryonic stem cells into the three germ layers.
As part of the Epigenome Roadmap project, this study uses a chromosome-spanning haplotype reconstruction strategy to construct haplotype-resolved epigenomic maps for a diverse set of human tissues; the maps reveal extensive allelic biases in chromatin state and transcription, which vary across individuals due to genetic backgrounds.
The integrative analysis of epigenetic footprints along consecutive stages of neural progenitors derived from human ES cells reveals regulatory mechanisms that orchestrate stage-specific differentiation.
An analysis of cell-type-specific epigenomic features reveals a relationship between epigenomic and mutational profiles; chromatin characteristics can explain a large proportion of mutational variance in cancer genomes and the mutational distribution can identify the probable cell type from which a given cancer originated from.
Alzheimer’s disease (AD) is a severe age-related neurodegenerative disorder characterized by accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions.
Comprehensive genome sequencing of 120 individuals representing all of the Darwin’s finch species and two close relatives reveals important discrepancies with morphology-based taxonomy, widespread hybridization, and a gene, ALX1, underlying variation in beak shape.
Mediator is the key transcription co-activator complex that enables basal and regulated transcription initiation by RNA polymerase (Pol) II; here a 15-subunit yeast core Mediator bound to a core Pol II initiation complex is reconstituted and its structure determined by cryo-electron microscopy at subnanometre resolution.
The origin of lithium is key to understanding the enrichment history of the Universe; now the classical nova V339 Del (Nova Delphini 2013) reveals that nova explosions could have been contributing to the recent rapid increase of the amount of lithium in the Universe.
Time-resolved X-ray solution scattering is used to visualize and probe the dynamics of the individual steps in the formation of a gold trimer complex, including covalent bond formation, with a time resolution of ~500 femtoseconds.
An ensemble of climate models shows that by the end of the twenty-first century the coastal upwelling season near the eastern boundaries of the Atlantic and Pacific oceans will start earlier, end later and become more intense at high latitudes, thus becoming more homogeneous; these changes may affect the geographical distribution of marine biodiversity.
Processes of melt generation and transport beneath back-arc spreading centres are controlled by two endmember mechanisms: decompression melting similar to that at mid-ocean ridges and flux melting resembling that beneath arcs. The Lau Basin, with an abundance of spreading ridges at different distances from the subduction zone, provides an opportunity to distinguish the effects of these two different melting processes on magma production and crust formation. Here we present constraints on the three-dimensional distribution of partial melt inferred from seismic velocities obtained from Rayleigh wave tomography using land and ocean-bottom seismographs. Low seismic velocities beneath the Central Lau Spreading Centre and the northern Eastern Lau Spreading Centre extend deeper and westwards into the back-arc, suggesting that these spreading centres are fed by melting along upwelling zones from the west, and helping to explain geochemical differences with the Valu Fa Ridge to the south, which has no distinct deep low-seismic-velocity anomalies. A region of low S-wave velocity, interpreted as resulting from high melt content, is imaged in the mantle wedge beneath the Central Lau Spreading Centre and the northeastern Lau Basin, even where no active spreading centre currently exists. This low-seismic-velocity anomaly becomes weaker with distance southward along the Eastern Lau Spreading Centre and the Valu Fa Ridge, in contrast to the inferred increase in magmatic productivity. We propose that the anomaly variations result from changes in the efficiency of melt extraction, with the decrease in melt to the south correlating with increased fractional melting and higher water content in the magma. Water released from the slab may greatly reduce the melt viscosity or increase grain size, or both, thereby facilitating melt transport.
In complex networks of the cerebral cortex, the majority of connections are weak and only a minority strong, but it is not known why; here the authors show that excitatory neurons in primary visual cortex follow a rule by which strong connections are sparse and occur between neurons with correlated responses to visual stimuli, whereas only weak connections link neurons with uncorrelated responses.
Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase σ (PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPσ has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.
Angelman syndrome is a neurodevelopmental disorder caused by disrupted function of the maternal copy of the imprinted UBE3A gene; here, targeting a long non-coding RNA that is responsible for silencing the paternal copy of UBE3A with antisense oligonucleotides is shown to partially restore UBE3A expression in the central nervous system and correct some cognitive deficits in a mouse model of the disease.
The role of cellular metabolism in regulating cell proliferation and differentiation remains poorly understood. For example, most mammalian cells cannot proliferate without exogenous glutamine supplementation even though glutamine is a non-essential amino acid. Here we show that mouse embryonic stem (ES) cells grown under conditions that maintain naive pluripotency are capable of proliferation in the absence of exogenous glutamine. Despite this, ES cells consume high levels of exogenous glutamine when the metabolite is available. In comparison to more differentiated cells, naive ES cells utilize both glucose and glutamine catabolism to maintain a high level of intracellular α-ketoglutarate (αKG). Consequently, naive ES cells exhibit an elevated αKG to succinate ratio that promotes histone/DNA demethylation and maintains pluripotency. Direct manipulation of the intracellular αKG/succinate ratio is sufficient to regulate multiple chromatin modifications, including H3K27me3 and ten-eleven translocation (Tet)-dependent DNA demethylation, which contribute to the regulation of pluripotency-associated gene expression. In vitro, supplementation with cell-permeable αKG directly supports ES-cell self-renewal while cell-permeable succinate promotes differentiation. This work reveals that intracellular αKG/succinate levels can contribute to the maintenance of cellular identity and have a mechanistic role in the transcriptional and epigenetic state of stem cells.
The deubiquitinase enzyme DUBA is shown to act as a negative regulator of interleukin-17A (IL-17A) in TH17 cells; DUBA interacts with and stabilizes the ubiquitin ligase UBR5, which in turn targets RORγt for degradation in the proteaseome, thus limiting IL-17A production.
Deep-genome and single-cell sequencing analyses of patient-derived breast cancer xenografts reveal extensive, dynamic and reproducible changes in intra-tumoral mutational clonal composition on engraftment and serial propagation.
Four different XNAs — polymers with backbone chemistries not found in nature, namely, arabino nucleic acids, 2′-fluoroarabino nucleic acids, hexitol nucleic acids and cyclohexene nucleic acids — are found to be able to support the evolution of synthetic enzymes (XNAzymes) that catalyse several chemical reactions.
Time-resolved resonance Raman vibrational spectroscopy was used to study the mechanism of soluble methane monooxygenase and obtain structural information on the key reaction cycle intermediate, compound Q, which contains a unique binuclear FeIV cluster that breaks the strong C-H bond of methane and inserts an oxygen atom (from O2) to form methanol.
The X-ray crystal structure of the human cytoplasmic dynein-2 motor bound to the ATP-hydrolysis transition state analogue ADP.vanadate is described.