目次

Editorials

健常者と患者の組織の大規模なエピゲノム研究によって、遺伝的差異と病気の結び付きの解明に役立つ重要な情報が得られるだろう。

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

Natureと月刊のNature関連誌では、従来の査読に加えてダブル・ブラインドの査読を導入し、著者が選択できるようにする。

Nature journals offer double-blind review p.274

doi: 10.1038/518274b

科学には、若々しい革新的思考と苦労して積み重ねた経験の組み合わせが必要だ。

The idea factory p.274

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

doi: 10.1038/518274a

News

サウジアラビアでも、最先端のアト秒レーザー装置が稼働へ。

Saudi Arabia opens top-notch laser lab p.281

Facility will study biomedical uses at attosecond resolution.

doi: 10.1038/518281a

ユーザーの人的要因への取り組みが、サイバー犯罪対策の課題に。

Cybercrime fighters target human error p.282

Researchers aim to cut passwords and people out of the data-safety equation.

doi: 10.1038/518282a

革新的な生物医学研究は若手科学者から生まれやすい傾向があることが、多数の論文の分析によって明らかに。

Young scientists lead the way on fresh ideas p.283

Analysis of millions of papers finds that junior biomedical researchers tend to work on more innovative topics than their senior colleagues do.

doi: 10.1038/518283a

古代DNAの解析から、インド・ヨーロッパ語族の起源は、ユーラシア草原地帯にあるとの説が有力に。

Steppe migration rekindles debate on language origin p.284

Eurasian region gains ground as birthplace of Indo-European tongues.

doi: 10.1038/518284a

ヒトの体のモデルとして、臓器チップとそのネットワーク化の研究が。

Biodefence researchers seek 'Homo chippiens' p.285

Projects aim to mimic human body using networks of simulated organs.

doi: 10.1038/518285a

政府からの助成が呼び水となって、米国エネルギー高等研究計画局(ARPA-E)の革新的エネルギー技術に多額の民間投資が。

Radical energy ideas secure US private funds p.286

Federal start-up funds inspire investment in ARPA-E technologies.

doi: 10.1038/518286a

News Features

ヒトの生物学:性別の再定義

Sex redefined p.288

性を2種類とする定義は単純に過ぎ、生物学的にもっと幅広いスペクトルがあることが分かってきた。

doi: 10.1038/518288a

博物館の収蔵品:生物標本の危機

Museums: The endangered dead p.292

地球で減少していく生物多様性を追跡するためにも、自然史博物館に収められた多数の標本の重要性は増しているが、今、標本そのものが危機に瀕している。

doi: 10.1038/518292a

News & Views

神経科学:皮質ニューロンの結合状態

Neuroscience: The cortical connection p.306

脳の視覚野中にあるニューロンは他の非常に多くのニューロンからの入力を受け取っている。しかし、個々のニューロンが強く結合しているのは、自己に最もよく似ている少数のニューロンだけであることが今回明らかになった。

doi: 10.1038/nature14201

宇宙物理学:リチウムに富む星の爆発

Astrophysics: A lithium-rich stellar explosion p.307

新星と呼ばれる爆発が、天の川銀河に含まれるリチウムの量にどの程度寄与しているのかははっきりしていない。このような爆発の1つに、崩壊してリチウムになる放射性ベリリウムが初めて検出された。

doi: 10.1038/518307a

進化:フィンチのゲノム塩基配列を解読

Evolution: Finches sequenced p.308

ダーウィンフィンチ類のゲノムの特徴が初めて詳細に調べられ、ダーウィンフィンチ類の15種全部と近縁の2種の120個体でゲノム塩基配列が明らかにされた。

doi: 10.1038/518308a

生化学:メタンの分解

Biochemistry: Breaking methane p.309

自然界に見られる最強の酸化剤は化合物Q、つまりメタンを酸化する酵素反応で生じる中間体である。新たに得られた分光学的データから、Qの化学構造についてのずっと続いてきた論争が解決された。

doi: 10.1038/nature14199

気候科学:海洋の沿岸湧昇はこれからどうなる?

Climate science: The future of coastal ocean upwelling p.310

気候モデルのアンサンブルによって、沿岸域に沿って吹く風は地球温暖化のために今後は強くなり、沿岸湧昇の規模がさらに拡大すると予想された。この過程は、沿岸域の海洋生態系の健全性に影響を及ぼす可能性がある。

doi: 10.1038/518310a

フォーラム:エピゲノミクス:調節エレメント解明のロードマップ

Epigenomics: Roadmap for regulation p.314

ヒト組織標品と細胞系列から得られたゲノムの機能性調節エレメントについて調べた一連の論文が発表された。このフォーラムでは、エピゲノムに関するこの研究計画の意味が、3つの視点から論じられている。

doi: 10.1038/518314a

Articles

エピゲノム:ヒトの参照エピゲノム111例の統合解析

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

エピゲノム:幹細胞分化の最中に起こるクロマチン構造の再編成

Chromatin architecture reorganization during stem cell differentiation OPEN p.331

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.

doi: 10.1038/nature14222

エピゲノム:自己免疫疾患の原因となるバリアントの遺伝学的およびエピジェネティックな精細マッピング

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

エピゲノム:ヒトES細胞の分化過程に見られる転写因子の結合動態

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

エピゲノム:多様なヒト組織にわたるハプロタイプ判定済みエピゲノムの統合解析

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

エピゲノム:エピジェネティックなフットプリンティングにより神経分化調節ネットワークを分析する

Dissecting neural differentiation regulatory networks through epigenetic footprinting p.355

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.

doi: 10.1038/nature13990

エピゲノム:起源細胞のクロマチン構成ががんの変異の特性を形作る

Cell-of-origin chromatin organization shapes the mutational landscape of cancer OPEN p.360

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.

doi: 10.1038/nature14221

エピゲノム:マウスとヒトで保存されているエピゲノムシグナルはアルツハイマー病の基盤への免疫の関連を明らかにしている

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

進化学:ゲノム塩基配列解読で明らかになったダーウィンフィンチ類とそのくちばしの進化

Evolution of Darwin’s finches and their beaks revealed by genome sequencing p.371

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.

doi: 10.1038/nature14181

分子生物学:RNAポリメラーゼII–メディエーターコア開始複合体の構造

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

宇宙物理学:古典新星V339 Del(いるか座新星2013)における爆発的リチウム生成

Explosive lithium production in the classical nova V339 Del (Nova Delphini 2013) p.381

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.

doi: 10.1038/nature14161

化学:フェムト秒X線散乱法による溶液中における結合形成の直接観察

Direct observation of bond formation in solution with femtosecond X-ray scattering p.385

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.

doi: 10.1038/nature14163

気候科学:気候変動下での沿岸湧昇の増強と空間的均一化

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

地球物理学:ラウ背弧マントルのメルト輸送に及ぼす水の影響の地震学的証拠

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

神経科学:一次視覚野の興奮性シナプス強度の機能的構成

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

神経科学:プロテオグリカン受容体PTPσの調節が脊髄損傷後の回復を促進する

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

創薬:Angelman症候群に対する、長鎖非コードRNAを標的とする治療法の開発

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

細胞生物学:細胞内α-ケトグルタル酸が胚性幹細胞の多能性を維持している

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

免疫学:脱ユビキチン化酵素DUBAは、T細胞でインターロイキン17産生を抑制する翻訳後ブレーキである

Deubiquitinase DUBA is a post-translational brake on interleukin-17 production in T cells p.417

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.

doi: 10.1038/nature13979

がん:乳がん患者の異種移植片におけるゲノムクローンの1細胞レベル分解能で見た動態

Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution p.422

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.

doi: 10.1038/nature13952

化学生物学:合成遺伝物質ポリマー由来の触媒

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

生化学:メタンからメタノールへの酵素的酸化で重要な化学種の構造

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

構造生物学:パワーストロークを起こせる状態にあるヒト細胞質ダイニン2の構造

Structure of human cytoplasmic dynein-2 primed for its power stroke p.435

The X-ray crystal structure of the human cytoplasmic dynein-2 motor bound to the ATP-hydrolysis transition state analogue ADP.vanadate is described.

doi: 10.1038/nature14023

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