Volume 518 Number 7539

Editorials

Beyond the genome p.273

Studies of the epigenomic signatures of many healthy and diseased human tissues could provide crucial infomation to link genetic variation and disease.

doi: 10.1038/518273a

The idea factory p.274

Science will benefit most from a combination of youthful innovation and hard-won experience.

doi: 10.1038/518274a

News

News Features

Sex redefined p.288

The idea of two sexes is simplistic. Biologists now think there is a wider spectrum than that.

doi: 10.1038/518288a

The endangered dead p.292

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.

doi: 10.1038/518292a

News & Views

The cortical connection p.306

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

doi: 10.1038/nature14201

A lithium-rich stellar explosion p.307

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

doi: 10.1038/518307a

Breaking methane p.309

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

doi: 10.1038/nature14199

The future of coastal ocean upwelling p.310

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

doi: 10.1038/518310a

Roadmap for regulation p.314

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

doi: 10.1038/518314a

Articles

Integrative analysis of 111 reference human epigenomes OPEN p.317

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.

doi: 10.1038/nature14248

Genetic and epigenetic fine mapping of causal autoimmune disease variants p.337

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.

doi: 10.1038/nature13835

Transcription factor binding dynamics during human ES cell differentiation OPEN p.344

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.

doi: 10.1038/nature14233

Letters

Integrative analysis of haplotype-resolved epigenomes across human tissues OPEN p.350

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.

doi: 10.1038/nature14217

Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease OPEN p.365

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.

doi: 10.1038/nature14252

Articles

Architecture of the RNA polymerase II–Mediator core initiation complex p.376

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.

doi: 10.1038/nature14229

Letters

Intensification and spatial homogenization of coastal upwelling under climate change p.390

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.

doi: 10.1038/nature14235

Seismic evidence of effects of water on melt transport in the Lau back-arc mantle p.395

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.

doi: 10.1038/nature14113

Functional organization of excitatory synaptic strength in primary visual cortex p.399

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.

doi: 10.1038/nature14182

Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury p.404

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.

doi: 10.1038/nature13974

Towards a therapy for Angelman syndrome by targeting a long non-coding RNA p.409

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.

doi: 10.1038/nature13975

Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells p.413

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.

doi: 10.1038/nature13981

Catalysts from synthetic genetic polymers p.427

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.

doi: 10.1038/nature13982

Structure of the key species in the enzymatic oxidation of methane to methanol p.431

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.

doi: 10.1038/nature14160