目次

Editorials

ねつ造事件を引き起こした韓国の黃禹錫の復権には、慎重な姿勢が必要だ。

Don’t rush to rehabilitate Hwang p.453

Nature’s profile of a former fraudster’s attempts to regain respectability should not be taken as an endorsement of the researcher’s claims.

doi: 10.1038/505453a

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米議会は、予算の空白を再び作らぬよう、今回の混乱を教訓にすべきだ。

A return to order p.453

Members of the US Congress have taken a much-needed step to restore credibility.

doi: 10.1038/505453b

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ストロンチウム原子を用いた新しい光学時計は精度が極めて高く、非常に安定で、時間の定義を見直すことにつながる可能性もある。

A question of time p.454

Timekeeping is boosted by the advent of an optical clock based on strontium atoms.

doi: 10.1038/505454a

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News

混乱を極めた米国の予算協議が、ついに決着。

Budget offers recovery hope p.461

US physical sciences benefit more than biomedical research.

doi: 10.1038/505461a

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英国の南極掘削計画の失敗の原因が詳細な解析で明らかになり、解決に望みも。

Polar drilling problems revealed p.463

Report into failings of expedition to explore Antarctic lake finds equipment to blame — but complications can be fixed.

doi: 10.1038/505463a

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カンラン石を利用した炭素隔離技術の改良に、研究者たちが関心を。

Rock’s power to mop up carbon revisited p.464

Experts push for more research into olivine weathering.

doi: 10.1038/505464a

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米イエローストーン国立公園のハイイログマが、保護の対象から外される恐れが。

Yellowstone grizzlies face losing protected status p.465

Conservationists protest after panel recommends ending bears’ endangered-species listing.

doi: 10.1038/505465a

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地質学的に重要な場所とされる南シナ海で、統合国際深海掘削計画(IODP)による掘削調査が。

Sea drilling project launches p.466

International expedition hopes to unravel mysteries of the South China Sea, one of the world’s most geologically important seas.

doi: 10.1038/505466a

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News Features

幹細胞:クローニングの返り咲き

Cloning comeback p.468

8年前、ねつ造と倫理問題で、ヒト幹細胞研究の頂点の座から滑り落ちた黃禹錫は、科学界で再び名誉を回復できるのだろうか。

doi: 10.1038/505468a

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量子物理学:傷まで完璧

Quantum physics: Flawed to perfection p.472

超高純度ダイヤモンドは、量子コンピューターから生物医学センサーまで、さまざまな分野を進歩させる。

doi: 10.1038/505472a

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News & Views

生態学:良き友がもたらす良い土

Ecology: Good dirt with good friends p.486

全球の森林にわたるデータの解析から、樹木の根に付く有益な真菌の種類によって、土壌中に蓄えられる炭素の量が決まることが明らかになった。

doi: 10.1038/nature12849

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太陽系:気化する小惑星

Solar system: Evaporating asteroid p.487

小惑星ケレスには大量の水が存在すると考えられている。ハーシェル宇宙望遠鏡によって行われた観測によって、太陽系のこの天体の表面から水蒸気が噴き出していることが分かった。

doi: 10.1038/505487a

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幹細胞:血液に見られる性的特異性

Stem cells: Sex specificity in the blood p.488

血液細胞を生み出す造血幹細胞はエストロゲンに応答し、そのため雌マウスでの細胞分裂頻度は雄マウスの場合よりも高いことが示された。これは、雌では妊娠中に血液の必要量が増えることに対しての備えであると考えられる。

doi: 10.1038/505488a

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電子工学:弱者を強者から守る

Electronics: Protecting the weak from the strong p.490

高感度の電子装置を強力な信号干渉から守ることができる、薄くて高性能の表面が開発された。これを使えば、高感度電子装置と外部アンテナとの効率的な通信が可能になる。

doi: 10.1038/nature12852

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気候科学:南極についてのパラドックスを解く

Climate science: A resolution of the Antarctic paradox p.491

南極風と海氷の変化を駆動するのに、北大西洋と熱帯大西洋が10年以上の規模の時間スケールで関わっている可能性が、観測データとモデリングを組み合わせることで示された。

doi: 10.1038/505491a

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HIV:あまり無害とは言えない隣人たち

HIV: Not-so-innocent bystanders p.492

HIV感染中に引き起こされるCD4+ T細胞の細胞死のほとんどは、ピロトーシスが原因であることが分かった。HIVに関連して起こるT細胞数の激減と炎症の原因はずっと不明のままだったが、この知見はそれについての説明になりそうだ。

doi: 10.1038/505492a

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Articles

がんゲノミクス:21種類の腫瘍におけるがん遺伝子の発見とサンプリング飽和度分析

Discovery and saturation analysis of cancer genes across 21 tumour types p.495

Large-scale genomic analysis of somatic point mutations in exomes from tumour–normal pairs across 21 cancer types identifies most known cancer genes in these tumour types as well as 33 genes not known to be significantly mutated, and down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies.

doi: 10.1038/nature12912

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免疫:SIVおよびHIVに対するワクチンを使った防御の免疫学的およびウイルス学的機構

Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV p.502

The analysis of multiple SIV vaccine regimens in macaques leads to the identification of a key two-amino-acid signature that confers resistance to neutralizing antibodies; a similar mechanism of immune escape is shown to operate in HIV and may explain the limited efficacy seen in HIV vaccine trials.

doi: 10.1038/nature12893

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免疫:HIV-1感染ではピロトーシスによる細胞死がCD4 T細胞枯渇を促進する

Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection p.509

Quiescent CD4 T cells in lymphoid tissues are shown to die after HIV-1 infection by caspase-1-mediated pyroptosis, a highly inflammatory form of programmed cell death; caspase 1 inhibitors, which are safe for human use, can rescue the cell death in vitro raising the possibility of new therapeutics targeting the host instead of the virus.

doi: 10.1038/nature12940

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構造生物学:哺乳類ミトコンドリアリボソームの大サブユニットの構造

Architecture of the large subunit of the mammalian mitochondrial ribosome p.515

Cryo-electron microscopy combined with chemical crosslinking and mass spectrometry is used to determine the structure of the large subunit of the mammalian mitoribosome; this structure provides detailed structural insight, particularly of the molecular architecture of the polypeptide exit site, which has been structurally remodelled during evolution, presumably to help facilitate the membrane insertion of the highly hydrophobic proteins encoded by the mitochondrial genome.

doi: 10.1038/nature12890

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Letters

宇宙:三重星系におけるミリ秒パルサー

A millisecond pulsar in a stellar triple system p.520

Gravitationally bound three-body systems have been studied for hundreds of years and are common in our Galaxy. They show complex orbital interactions, which can constrain the compositions, masses and interior structures of the bodies and test theories of gravity, if sufficiently precise measurements are available. A triple system containing a radio pulsar could provide such measurements, but the only previously known such system, PSR B1620-26 (refs 7, 8; with a millisecond pulsar, a white dwarf, and a planetary-mass object in an orbit of several decades), shows only weak interactions. Here we report precision timing and multiwavelength observations of PSR J0337+1715, a millisecond pulsar in a hierarchical triple system with two other stars. Strong gravitational interactions are apparent and provide the masses of the pulsar (1.4378(13), where is the solar mass and the parentheses contain the uncertainty in the final decimal places) and the two white dwarf companions (0.19751(15) and 0.4101(3)), as well as the inclinations of the orbits (both about 39.2°). The unexpectedly coplanar and nearly circular orbits indicate a complex and exotic evolutionary past that differs from those of known stellar systems. The gravitational field of the outer white dwarf strongly accelerates the inner binary containing the neutron star, and the system will thus provide an ideal laboratory in which to test the strong equivalence principle of general relativity.

doi: 10.1038/nature12917

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宇宙:準惑星(1)ケレス表面にある局在化した水蒸気発生源

Localized sources of water vapour on the dwarf planet (1) Ceres p.525

The ‘snowline’ conventionally divides Solar System objects into dry bodies, ranging out to the main asteroid belt, and icy bodies beyond the belt. Models suggest that some of the icy bodies may have migrated into the asteroid belt. Recent observations indicate the presence of water ice on the surface of some asteroids, with sublimation a potential reason for the dust activity observed on others. Hydrated minerals have been found on the surface of the largest object in the asteroid belt, the dwarf planet (1) Ceres, which is thought to be differentiated into a silicate core with an icy mantle. The presence of water vapour around Ceres was suggested by a marginal detection of the photodissociation product of water, hydroxyl (ref. 12), but could not be confirmed by later, more sensitive observations. Here we report the detection of water vapour around Ceres, with at least 1026 molecules being produced per second, originating from localized sources that seem to be linked to mid-latitude regions on the surface. The water evaporation could be due to comet-like sublimation or to cryo-volcanism, in which volcanoes erupt volatiles such as water instead of molten rocks.

doi: 10.1038/nature12918

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量子エレクトロニクス:グラフェン量子スピンホール状態における可変な対称性の破れとヘリカルエッジ輸送

Tunable symmetry breaking and helical edge transport in a graphene quantum spin Hall state p.528

Low-dimensional electronic systems have traditionally been obtained by electrostatically confining electrons, either in heterostructures or in intrinsically nanoscale materials such as single molecules, nanowires and graphene. Recently, a new method has emerged with the recognition that symmetry-protected topological (SPT) phases, which occur in systems with an energy gap to quasiparticle excitations (such as insulators or superconductors), can host robust surface states that remain gapless as long as the relevant global symmetry remains unbroken. The nature of the charge carriers in SPT surface states is intimately tied to the symmetry of the bulk, resulting in one- and two-dimensional electronic systems with novel properties. For example, time reversal symmetry endows the massless charge carriers on the surface of a three-dimensional topological insulator with helicity, fixing the orientation of their spin relative to their momentum. Weakly breaking this symmetry generates a gap on the surface, resulting in charge carriers with finite effective mass and exotic spin textures. Analogous manipulations have yet to be demonstrated in two-dimensional topological insulators, where the primary example of a SPT phase is the quantum spin Hall state. Here we demonstrate experimentally that charge-neutral monolayer graphene has a quantum spin Hall state when it is subjected to a very large magnetic field angled with respect to the graphene plane. In contrast to time-reversal-symmetric systems, this state is protected by a symmetry of planar spin rotations that emerges as electron spins in a half-filled Landau level are polarized by the large magnetic field. The properties of the resulting helical edge states can be modulated by balancing the applied field against an intrinsic antiferromagnetic instability, which tends to spontaneously break the spin-rotation symmetry. In the resulting canted antiferromagnetic state, we observe transport signatures of gapped edge states, which constitute a new kind of one-dimensional electronic system with a tunable bandgap and an associated spin texture.

doi: 10.1038/nature12800

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材料:2層グラフェンにおける転位

Dislocations in bilayer graphene p.533

Dislocations represent one of the most fascinating and fundamental concepts in materials science. Most importantly, dislocations are the main carriers of plastic deformation in crystalline materials. Furthermore, they can strongly affect the local electronic and optical properties of semiconductors and ionic crystals. In materials with small dimensions, they experience extensive image forces, which attract them to the surface to release strain energy. However, in layered crystals such as graphite, dislocation movement is mainly restricted to the basal plane. Thus, the dislocations cannot escape, enabling their confinement in crystals as thin as only two monolayers. To explore the nature of dislocations under such extreme boundary conditions, the material of choice is bilayer graphene, the thinnest possible quasi-two-dimensional crystal in which such linear defects can be confined. Homogeneous and robust graphene membranes derived from high-quality epitaxial graphene on silicon carbide provide an ideal platform for their investigation. Here we report the direct observation of basal-plane dislocations in freestanding bilayer graphene using transmission electron microscopy and their detailed investigation by diffraction contrast analysis and atomistic simulations. Our investigation reveals two striking size effects. First, the absence of stacking-fault energy, a unique property of bilayer graphene, leads to a characteristic dislocation pattern that corresponds to an alternating AB  AC change of the stacking order. Second, our experiments in combination with atomistic simulations reveal a pronounced buckling of the bilayer graphene membrane that results directly from accommodation of strain. In fact, the buckling changes the strain state of the bilayer graphene and is of key importance for its electronic properties. Our findings will contribute to the understanding of dislocations and of their role in the structural, mechanical and electronic properties of bilayer and few-layer graphene.

doi: 10.1038/nature12780

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気候:北大西洋と熱帯大西洋がもたらす南極半島と海氷への影響

Impacts of the north and tropical Atlantic Ocean on the Antarctic Peninsula and sea ice p.538

In recent decades, Antarctica has experienced pronounced climate changes. The Antarctic Peninsula exhibited the strongest warming of any region on the planet, causing rapid changes in land ice. Additionally, in contrast to the sea-ice decline over the Arctic, Antarctic sea ice has not declined, but has instead undergone a perplexing redistribution. Antarctic climate is influenced by, among other factors, changes in radiative forcing and remote Pacific climate variability, but none explains the observed Antarctic Peninsula warming or the sea-ice redistribution in austral winter. However, in the north and tropical Atlantic Ocean, the Atlantic Multidecadal Oscillation (a leading mode of sea surface temperature variability) has been overlooked in this context. Here we show that sea surface warming related to the Atlantic Multidecadal Oscillation reduces the surface pressure in the Amundsen Sea and contributes to the observed dipole-like sea-ice redistribution between the Ross and Amundsen–Bellingshausen–Weddell seas and to the Antarctic Peninsula warming. Support for these findings comes from analysis of observational and reanalysis data, and independently from both comprehensive and idealized atmospheric model simulations. We suggest that the north and tropical Atlantic is important for projections of future climate change in Antarctica, and has the potential to affect the global thermohaline circulation and sea-level change.

doi: 10.1038/nature12945

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生態:菌根が介在する植物と分解者との競争が土壌炭素の貯蔵を促進する

Mycorrhiza-mediated competition between plants and decomposers drives soil carbon storage p.543

Soil contains more carbon than the atmosphere and vegetation combined. Understanding the mechanisms controlling the accumulation and stability of soil carbon is critical to predicting the Earth’s future climate. Recent studies suggest that decomposition of soil organic matter is often limited by nitrogen availability to microbes and that plants, via their fungal symbionts, compete directly with free-living decomposers for nitrogen. Ectomycorrhizal and ericoid mycorrhizal (EEM) fungi produce nitrogen-degrading enzymes, allowing them greater access to organic nitrogen sources than arbuscular mycorrhizal (AM) fungi. This leads to the theoretical prediction that soil carbon storage is greater in ecosystems dominated by EEM fungi than in those dominated by AM fungi. Using global data sets, we show that soil in ecosystems dominated by EEM-associated plants contains 70% more carbon per unit nitrogen than soil in ecosystems dominated by AM-associated plants. The effect of mycorrhizal type on soil carbon is independent of, and of far larger consequence than, the effects of net primary production, temperature, precipitation and soil clay content. Hence the effect of mycorrhizal type on soil carbon content holds at the global scale. This finding links the functional traits of mycorrhizal fungi to carbon storage at ecosystem-to-global scales, suggesting that plant–decomposer competition for nutrients exerts a fundamental control over the terrestrial carbon cycle.

doi: 10.1038/nature12901

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作物学:近年新しく栽培化された作物テンサイのゲノム

The genome of the recently domesticated crop plant sugar beet (Beta vulgaris) OPEN p.546

Sugar beet (Beta vulgaris ssp. vulgaris) is an important crop of temperate climates which provides nearly 30% of the world’s annual sugar production and is a source for bioethanol and animal feed. The species belongs to the order of Caryophylalles, is diploid with 2n = 18 chromosomes, has an estimated genome size of 714–758 megabases and shares an ancient genome triplication with other eudicot plants. Leafy beets have been cultivated since Roman times, but sugar beet is one of the most recently domesticated crops. It arose in the late eighteenth century when lines accumulating sugar in the storage root were selected from crosses made with chard and fodder beet. Here we present a reference genome sequence for sugar beet as the first non-rosid, non-asterid eudicot genome, advancing comparative genomics and phylogenetic reconstructions. The genome sequence comprises 567 megabases, of which 85% could be assigned to chromosomes. The assembly covers a large proportion of the repetitive sequence content that was estimated to be 63%. We predicted 27,421 protein-coding genes supported by transcript data and annotated them on the basis of sequence homology. Phylogenetic analyses provided evidence for the separation of Caryophyllales before the split of asterids and rosids, and revealed lineage-specific gene family expansions and losses. We sequenced spinach (Spinacia oleracea), another Caryophyllales species, and validated features that separate this clade from rosids and asterids. Intraspecific genomic variation was analysed based on the genome sequences of sea beet (Beta vulgaris ssp. maritima; progenitor of all beet crops) and four additional sugar beet accessions. We identified seven million variant positions in the reference genome, and also large regions of low variability, indicating artificial selection. The sugar beet genome sequence enables the identification of genes affecting agronomically relevant traits, supports molecular breeding and maximizes the plant’s potential in energy biotechnology.

doi: 10.1038/nature12817

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神経科学:ホスホリパーゼD3遺伝子のまれなコーディング変異がアルツハイマー病のリスクとなる

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease p.550

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case–control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer’s disease in seven independent case–control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer’s disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer’s disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer’s disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.

doi: 10.1038/nature12825

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細胞:エストロゲンは雌で、また妊娠中に造血幹細胞の自己複製を増加させる

Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy p.555

Sexually dimorphic mammalian tissues, including sexual organs and the brain, contain stem cells that are directly or indirectly regulated by sex hormones. An important question is whether stem cells also exhibit sex differences in physiological function and hormonal regulation in tissues that do not show sex-specific morphological differences. The terminal differentiation and function of some haematopoietic cells are regulated by sex hormones, but haematopoietic stem-cell function is thought to be similar in both sexes. Here we show that mouse haematopoietic stem cells exhibit sex differences in cell-cycle regulation by oestrogen. Haematopoietic stem cells in female mice divide significantly more frequently than in male mice. This difference depends on the ovaries but not the testes. Administration of oestradiol, a hormone produced mainly in the ovaries, increased haematopoietic stem-cell division in males and females. Oestrogen levels increased during pregnancy, increasing haematopoietic stem-cell division, haematopoietic stem-cell frequency, cellularity, and erythropoiesis in the spleen. Haematopoietic stem cells expressed high levels of oestrogen receptor-α (ERα). Conditional deletion of ERα from haematopoietic stem cells reduced haematopoietic stem-cell division in female, but not male, mice and attenuated the increases in haematopoietic stem-cell division, haematopoietic stem-cell frequency, and erythropoiesis during pregnancy. Oestrogen/ERα signalling promotes haematopoietic stem-cell self-renewal, expanding splenic haematopoietic stem cells and erythropoiesis during pregnancy.

doi: 10.1038/nature12932

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微生物学:食餌は、ヒトの腸内微生物叢を迅速に高い再現性をもって変化させる

Diet rapidly and reproducibly alters the human gut microbiome p.559

Long-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut, but it remains unclear how rapidly and reproducibly the human gut microbiome responds to short-term macronutrient change. Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease. In concert, these results demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles.

doi: 10.1038/nature12820

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分子生物学:ヒストンH2A中のグルタミンメチル化はRNAポリメラーゼIのためだけの修飾である

Glutamine methylation in histone H2A is an RNA-polymerase-I-dedicated modification p.564

Nucleosomes are decorated with numerous post-translational modifications capable of influencing many DNA processes. Here we describe a new class of histone modification, methylation of glutamine, occurring on yeast histone H2A at position 105 (Q105) and human H2A at Q104. We identify Nop1 as the methyltransferase in yeast and demonstrate that fibrillarin is the orthologue enzyme in human cells. Glutamine methylation of H2A is restricted to the nucleolus. Global analysis in yeast, using an H2AQ105me-specific antibody, shows that this modification is exclusively enriched over the 35S ribosomal DNA transcriptional unit. We show that the Q105 residue is part of the binding site for the histone chaperone FACT (facilitator of chromatin transcription) complex. Methylation of Q105 or its substitution to alanine disrupts binding to FACT in vitro. A yeast strain mutated at Q105 shows reduced histone incorporation and increased transcription at the ribosomal DNA locus. These features are phenocopied by mutations in FACT complex components. Together these data identify glutamine methylation of H2A as the first histone epigenetic mark dedicated to a specific RNA polymerase and define its function as a regulator of FACT interaction with nucleosomes.

doi: 10.1038/nature12819

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構造生物学:胆汁酸輸送体における交互アクセス機構の構造基盤

Structural basis of the alternating-access mechanism in a bile acid transporter p.569

Bile acids are synthesized from cholesterol in hepatocytes and secreted through the biliary tract into the small intestine, where they aid in absorption of lipids and fat-soluble vitamins. Through a process known as enterohepatic recirculation, more than 90% of secreted bile acids are then retrieved from the intestine and returned to the liver for resecretion. In humans, there are two Na+-dependent bile acid transporters involved in enterohepatic recirculation, the Na+-taurocholate co-transporting polypeptide (NTCP; also known as SLC10A1) expressed in hepatocytes, and the apical sodium-dependent bile acid transporter (ASBT; also known as SLC10A2) expressed on enterocytes in the terminal ileum. In recent years, ASBT has attracted much interest as a potential drug target for treatment of hypercholesterolaemia, because inhibition of ASBT reduces reabsorption of bile acids, thus increasing bile acid synthesis and consequently cholesterol consumption. However, a lack of three-dimensional structures of bile acid transporters hampers our ability to understand the molecular mechanisms of substrate selectivity and transport, and to interpret the wealth of existing functional data. The crystal structure of an ASBT homologue from Neisseria meningitidis (ASBTNM) in detergent was reported recently, showing the protein in an inward-open conformation bound to two Na+ and a taurocholic acid. However, the structural changes that bring bile acid and Na+ across the membrane are difficult to infer from a single structure. To understand the structural changes associated with the coupled transport of Na+ and bile acids, here we solved two structures of an ASBT homologue from Yersinia frederiksenii (ASBTYf) in a lipid environment, which reveal that a large rigid-body rotation of a substrate-binding domain gives the conserved ‘crossover’ region, where two discontinuous helices cross each other, alternating accessibility from either side of the cell membrane. This result has implications for the location and orientation of the bile acid during transport, as well as for the translocation pathway for Na+.

doi: 10.1038/nature12811

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