네이처 컨텐츠

Editorials

Stem-cell fiasco must be stopped p.331

In the public interest, the Italian health minister should resolve the ongoing uncertainty over a government trial of a controversial therapy.

doi: 10.1038/504331a

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Sink or swim? p.331

A rethink on monitoring land-use change is needed to estimate effects on global warming.

doi: 10.1038/504331b

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Futures redux p.332

Can you tell a sci-fi tale in just 200 characters? Then the Nature Futures competition is for you.

doi: 10.1038/504332a

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News

EU fishing vote foments anger p.341

Failure to impose a ban on deep-sea fishing jeopardizes the future of vulnerable ecosystems, say researchers.

Daniel Cressey

doi: 10.1038/504341a

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Quandary over Soviet croplands p.342

Researchers ponder whether Eastern Europe’s large areas of abandoned land should be replanted or left as a carbon sink.

Quirin Schiermeier

doi: 10.1038/504342a

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2013 in review p.344

From the US shutdown to breakthroughs in stem-cell therapies, the past 12 months have seen fluctuating fortunes for science.

Richard Can Noorden, Jeff Tollefson, Erika Check Hayden, Lauren Moerello & Helen Shen

doi: 10.1038/504344a

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Images of the year p.350

Clear brains, hydrogen bonds and gas expelled from galaxies are among the most striking images of 2013.

Daniel Cressey

doi: 10.1038/504350a

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Feature

News & Views

Erosion by cooling p.380

The thermal history of thousands of rock samples convincingly confirms the idea that climate cooling accelerates the rate of erosion at Earth's surface — and implicates glaciers in particular. See Letter p.423

David Lundbek Egholm

doi: 10.1038/504380a

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Discrepancies in drug sensitivity p.381

Large panels of human cancer cell lines have been profiled at the DNA, RNA and pharmacological levels to accelerate the search for cancer therapies. But two of those large data sets show only partial concordance. See Analysis p.389

John N. Weinstein & Philip L. Lorenzi

doi: 10.1038/nature12839

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A fast lane in the magnetosphere p.383

A marriage between satellite observations and modelling has shown that acceleration of electrons in the magnetosphere can be explained by scattering of these particles by plasma oscillations known as chorus waves. See Letter p.411

Mary K. Hudson

doi: 10.1038/504383a

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Witchcraft and destruction p.384

The discovery of a protein that is targeted for degradation by the 'witch' hormones called strigolactones reveals a mechanism by which shoot architecture is controlled in rice plants. See Articles p.401 & p.406

Steven M. Smith

doi: 10.1038/nature12843

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Analysis

Inconsistency in large pharmacogenomic studies p.389

Two large-scale pharmacogenomic studies were published recently in this journal. Genomic data are well correlated between studies; however, the measured drug response data are highly discordant. Although the source of inconsistencies remains uncertain, it has potential implications for using these outcome measures to assess gene–drug associations or select potential anticancer drugs on the basis of their reported results.

Benjamin Haibe-Kains, Nehme El-Hachem, Nicolai Juul Birkbak, Andrew C. Jin, Andrew H. Beck, Hugo J. W. L. Aerts & John Quackenbush

doi: 10.1038/nature12831

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Articles

Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways p.394

This study describes comprehensive synaptic engulfment by astrocytes, mediating synapse elimination in an activity-dependent manner; this elimination process involves the MEGF10 and MERTK phagocytic pathways and persists into adulthood, with mutant mice that lack these pathways in astrocytes exhibiting a failure to refine retinogeniculate connections during development.

Won-Suk Chung, Laura E. Clarke, Gordon X. Wang, Benjamin K. Stafford, Alexander Sher, Chandrani Chakraborty, Julia Joung, Lynette C. Foo, Andrew Thompson, Chinfei Chen + et al.

doi: 10.1038/nature12776

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DWARF 53 acts as a repressor of strigolactone signalling in rice p.401

Strigolactones (SLs), key regulators of plant growth, are believed to mediate their responses through a proposed receptor (D14) that interacts with an F-box protein (D3) to form a D14–SCFD3 protein complex; here the perception of SLs by the D14–SCFD3 complex and the control of gene expression are linked by the finding that DWARF 53, a repressor protein of SL signalling, interacts with the D14–SCFD3 complex and is ubiquitinated and degraded in a SL-dependent manner.

Liang Jiang, Xue Liu, Guosheng Xiong, Huihui Liu, Fulu Chen, Lei Wang, Xiangbing Meng, Guifu Liu, Hong Yu, Yundong Yuan + et al.

doi: 10.1038/nature12870

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D14–SCFD3-dependent degradation of D53 regulates strigolactone signalling p.406

Strigolactones (SLs), key regulators of plant growth, are believed to mediate their responses through a proposed receptor (D14) that interacts with an F-box protein (D3) to form a D14–SCFD3 protein complex; here the perception of SLs by the D14–SCFD3 complex and the control of gene expression are linked by the finding that DWARF 53, a repressor protein of SL function, interacts with the D14–SCFD3 complex and is ubiquitinated and degraded in a SL-dependent manner.

Feng Zhou, Qibing Lin, Lihong Zhu, Yulong Ren, Kunneng Zhou, Nitzan Shabek, Fuqing Wu, Haibin Mao, Wei Dong, Lu Gan + et al.

doi: 10.1038/nature12878

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Letters

Rapid local acceleration of relativistic radiation-belt electrons by magnetospheric chorus p.411

Recent analysis of satellite data obtained during the 9 October 2012 geomagnetic storm identified the development of peaks in electron phase space density, which are compelling evidence for local electron acceleration in the heart of the outer radiation belt, but are inconsistent with acceleration by inward radial diffusive transport. However, the precise physical mechanism responsible for the acceleration on 9 October was not identified. Previous modelling has indicated that a magnetospheric electromagnetic emission known as chorus could be a potential candidate for local electron acceleration, but a definitive resolution of the importance of chorus for radiation-belt acceleration was not possible because of limitations in the energy range and resolution of previous electron observations and the lack of a dynamic global wave model. Here we report high-resolution electron observations obtained during the 9 October storm and demonstrate, using a two-dimensional simulation performed with a recently developed time-varying data-driven model, that chorus scattering explains the temporal evolution of both the energy and angular distribution of the observed relativistic electron flux increase. Our detailed modelling demonstrates the remarkable efficiency of wave acceleration in the Earth’s outer radiation belt, and the results presented have potential application to Jupiter, Saturn and other magnetized astrophysical objects.

R. M. Thorne, W. Li, B. Ni, Q. Ma, J. Bortnik, L. Chen, D. N. Baker, H. E. Spence, G. D. Reeves, M. G. Henderson + et al.

doi: 10.1038/nature12889

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Dissipative production of a maximally entangled steady state of two quantum bits p.415

Entangled states are a key resource in fundamental quantum physics, quantum cryptography and quantum computation. Introduction of controlled unitary processes—quantum gates—to a quantum system has so far been the most widely used method to create entanglement deterministically. These processes require high-fidelity state preparation and minimization of the decoherence that inevitably arises from coupling between the system and the environment, and imperfect control of the system parameters. Here we combine unitary processes with engineered dissipation to deterministically produce and stabilize an approximate Bell state of two trapped-ion quantum bits (qubits), independent of their initial states. Compared with previous studies that involved dissipative entanglement of atomic ensembles or the application of sequences of multiple time-dependent gates to trapped ions, we implement our combined process using trapped-ion qubits in a continuous time-independent fashion (analogous to optical pumping of atomic states). By continuously driving the system towards the steady state, entanglement is stabilized even in the presence of experimental noise and decoherence. Our demonstration of an entangled steady state of two qubits represents a step towards dissipative state engineering, dissipative quantum computation and dissipative phase transitions. Following this approach, engineered coupling to the environment may be applied to a broad range of experimental systems to achieve desired quantum dynamics or steady states. Indeed, concurrently with this work, an entangled steady state of two superconducting qubits was demonstrated using dissipation.

Y. Lin, J. P. Gaebler, F. Reiter, T. R. Tan, R. Bowler, A. S. Sørensen, D. Leibfried & D. J. Wineland

doi: 10.1038/nature12801

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Autonomously stabilized entanglement between two superconducting quantum bits p.419

Quantum error correction codes are designed to protect an arbitrary state of a multi-qubit register from decoherence-induced errors, but their implementation is an outstanding challenge in the development of large-scale quantum computers. The first step is to stabilize a non-equilibrium state of a simple quantum system, such as a quantum bit (qubit) or a cavity mode, in the presence of decoherence. This has recently been accomplished using measurement-based feedback schemes. The next step is to prepare and stabilize a state of a composite system. Here we demonstrate the stabilization of an entangled Bell state of a quantum register of two superconducting qubits for an arbitrary time. Our result is achieved using an autonomous feedback scheme that combines continuous drives along with a specifically engineered coupling between the two-qubit register and a dissipative reservoir. Similar autonomous feedback techniques have been used for qubit reset, single-qubit state stabilization, and the creation and stabilization of states of multipartite quantum systems. Unlike conventional, measurement-based schemes, the autonomous approach uses engineered dissipation to counteract decoherence, obviating the need for a complicated external feedback loop to correct errors. Instead, the feedback loop is built into the Hamiltonian such that the steady state of the system in the presence of drives and dissipation is a Bell state, an essential building block for quantum information processing. Such autonomous schemes, which are broadly applicable to a variety of physical systems, as demonstrated by the accompanying paper on trapped ion qubits, will be an essential tool for the implementation of quantum error correction.

S. Shankar, M. Hatridge, Z. Leghtas, K. M. Sliwa, A. Narla, U. Vool, S. M. Girvin, L. Frunzio, M. Mirrahimi & M. H. Devoret

doi: 10.1038/nature12802

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Worldwide acceleration of mountain erosion under a cooling climate p.423

Climate influences the erosion processes acting at the Earth’s surface. However, the effect of cooling during the Late Cenozoic era, including the onset of Pliocene–Pleistocene Northern Hemisphere glaciation (about two to three million years ago), on global erosion rates remains unclear. The uncertainty arises mainly from a lack of consensus on the use of the sedimentary record as a proxy for erosion and the difficulty of isolating the respective contributions of tectonics and climate to erosion. Here we compile 18,000 bedrock thermochronometric ages from around the world and use a formal inversion procedure to estimate temporal and spatial variations in erosion rates. This allows for the quantification of erosion for the source areas that ultimately produce the sediment record on a timescale of millions of years. We find that mountain erosion rates have increased since about six million years ago and most rapidly since two million years ago. The increase of erosion rates is observed at all latitudes, but is most pronounced in glaciated mountain ranges, indicating that glacial processes played an important part. Because mountains represent a considerable fraction of the global production of sediments, our results imply an increase in sediment flux at a global scale that coincides closely with enhanced cooling during the Pliocene and Pleistocene epochs.

Frédéric Herman, Diane Seward, Pierre G. Valla, Andrew Carter, Barry Kohn, Sean D. Willett & Todd A. Ehlers

doi: 10.1038/nature12877

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Attention to eyes is present but in decline in 2–6-month-old infants later diagnosed with autism p.427

Deficits in eye contact have been a hallmark of autism since the condition’s initial description. They are cited widely as a diagnostic feature and figure prominently in clinical instruments; however, the early onset of these deficits has not been known. Here we show in a prospective longitudinal study that infants later diagnosed with autism spectrum disorders (ASDs) exhibit mean decline in eye fixation from 2 to 6 months of age, a pattern not observed in infants who do not develop ASD. These observations mark the earliest known indicators of social disability in infancy, but also falsify a prior hypothesis: in the first months of life, this basic mechanism of social adaptive action—eye looking—is not immediately diminished in infants later diagnosed with ASD; instead, eye looking appears to begin at normative levels prior to decline. The timing of decline highlights a narrow developmental window and reveals the early derailment of processes that would otherwise have a key role in canalizing typical social development. Finally, the observation of this decline in eye fixation—rather than outright absence—offers a promising opportunity for early intervention that could build on the apparent preservation of mechanisms subserving reflexive initial orientation towards the eyes.

Warren Jones & Ami Klin

doi: 10.1038/nature12715

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Dysfunctional nitric oxide signalling increases risk of myocardial infarction p.432

Two private, heterozygous mutations in two functionally related genes, GUCY1A3 and CCT7, are identified in an extended family with myocardial infarction; these genes encode proteins that work together to inhibit platelet activation after nitric oxide stimulation, suggesting a link between impaired nitric oxide signalling and myocardial infarction risk.

Jeanette Erdmann, Klaus Stark, Ulrike B. Esslinger, Philipp Moritz Rumpf, Doris Koesling, Cor de Wit, Frank J. Kaiser, Diana Braunholz, Anja Medack, Marcus Fischer + et al.

doi: 10.1038/nature12722

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Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors p.437

Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate in pancreatic β-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production, and is subject to the endogenous inhibitor GK regulatory protein (GKRP). During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK–GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.

David J. Lloyd, David J. St Jean, Robert J. M. Kurzeja, Robert C. Wahl, Klaus Michelsen, Rod Cupples, Michelle Chen, John Wu, Glenn Sivits, Joan Helmering + et al.

doi: 10.1038/nature12724

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Themis sets the signal threshold for positive and negative selection in T-cell development p.441

Development of a self-tolerant T-cell receptor (TCR) repertoire with the potential to recognize the universe of infectious agents depends on proper regulation of TCR signalling. The repertoire is whittled down during T-cell development in the thymus by the ability of quasi-randomly generated TCRs to interact with self-peptides presented by major histocompatibility complex (MHC) proteins. Low-affinity TCR interactions with self-MHC proteins generate weak signals that initiate ‘positive selection’, causing maturation of CD4- or CD8αβ-expressing ‘single-positive’ thymocytes from CD4+CD8αβ+ ‘double-positive’ precursors. These develop into mature naive T cells of the secondary lymphoid organs. TCR interaction with high-affinity agonist self-ligands results in ‘negative selection’ by activation-induced apoptosis or ‘agonist selection’ of functionally differentiated self-antigen-experienced T cells. Here we show that positive selection is enabled by the ability of the T-cell-specific protein Themis to specifically attenuate TCR signal strength via SHP1 recruitment and activation in response to low- but not high-affinity TCR engagement. Themis acts as an analog-to-digital converter translating graded TCR affinity into clear-cut selection outcome. By dampening mild TCR signals Themis increases the affinity threshold for activation, enabling positive selection of T cells with a naive phenotype in response to low-affinity self-antigens.

Guo Fu, Javier Casas, Stephanie Rigaud, Vasily Rybakin, Florence Lambolez, Joanna Brzostek, John A. H. Hoerter, Wolfgang Paster, Oreste Acuto, Hilde Cheroutre + et al.

doi: 10.1038/nature12718

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Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells p.446

Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4+ CD45RBhi T cells in Rag1−/− mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host–microbe interactions establish immunological homeostasis in the gut.

Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda, Takaho A. Endo, Gaku Nakato, Daisuke Takahashi, Yumiko Nakanishi, Chikako Uetake, Keiko Kato, Tamotsu Kato + et al.

doi: 10.1038/nature12721

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Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation p.451

Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T cells (Treg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory T helper 17 (TH17) cells, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we reasoned that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We tested this hypothesis by exploring the effect of microbial metabolites on the generation of anti-inflammatory Treg cells. We found that in mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg-cell numbers after provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells, as the observed phenomenon was dependent on intronic enhancer CNS1 (conserved non-coding sequence 1), essential for extrathymic but dispensable for thymic Treg-cell differentiation. In addition to butyrate, de novo Treg-cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.

Nicholas Arpaia, Clarissa Campbell, Xiying Fan, Stanislav Dikiy, Joris van der Veeken, Paul deRoos, Hui Liu, Justin R. Cross, Klaus Pfeffer, Paul J. Coffer + et al.

doi: 10.1038/nature12726

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The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality p.456

Heterotaxy is a disorder of left–right body patterning, or laterality, that is associated with major congenital heart disease. The aetiology and mechanisms underlying most cases of human heterotaxy are poorly understood. In vertebrates, laterality is initiated at the embryonic left–right organizer, where motile cilia generate leftward flow that is detected by immotile sensory cilia, which transduce flow into downstream asymmetric signals. The mechanism that specifies these two cilia types remains unknown. Here we show that the N-acetylgalactosamine-type O-glycosylation enzyme GALNT11 is crucial to such determination. We previously identified GALNT11 as a candidate disease gene in a patient with heterotaxy, and now demonstrate, in Xenopus tropicalis, that galnt11 activates Notch signalling. GALNT11 O-glycosylates human NOTCH1 peptides in vitro, thereby supporting a mechanism of Notch activation either by increasing ADAM17-mediated ectodomain shedding of the Notch receptor or by modification of specific EGF repeats. We further developed a quantitative live imaging technique for Xenopus left–right organizer cilia and show that Galnt11-mediated Notch1 signalling modulates the spatial distribution and ratio of motile and immotile cilia at the left–right organizer. galnt11 or notch1 depletion increases the ratio of motile cilia at the expense of immotile cilia and produces a laterality defect reminiscent of loss of the ciliary sensor Pkd2. By contrast, Notch overexpression decreases this ratio, mimicking the ciliopathy primary ciliary dyskinesia. Together our data demonstrate that Galnt11 modifies Notch, establishing an essential balance between motile and immotile cilia at the left–right organizer to determine laterality, and reveal a novel mechanism for human heterotaxy.

Marko T. Boskovski, Shiaulou Yuan, Nis Borbye Pedersen, Christoffer Knak Goth, Svetlana Makova, Henrik Clausen, Martina Brueckner & Mustafa K. Khokha

doi: 10.1038/nature12723

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Role of Tet1 in erasure of genomic imprinting p.460

Genomic imprinting is an allele-specific gene expression system that is important for mammalian development and function. The molecular basis of genomic imprinting is allele-specific DNA methylation. Although it is well known that the de novo DNA methyltransferases Dnmt3a and Dnmt3b are responsible for the establishment of genomic imprinting, how the methylation mark is erased during primordial germ cell (PGC) reprogramming remains unclear. Tet1 is one of the ten-eleven translocation family proteins, which have the capacity to oxidize 5-methylcytosine (5mC), specifically expressed in reprogramming PGCs. Here we report that Tet1 has a critical role in the erasure of genomic imprinting. We show that despite their identical genotype, progenies derived from mating between Tet1 knockout males and wild-Peg10 and Peg3, which exhibit aberrant hypermethylation in the paternal allele of differential methylated regions (DMRs). RNA-seq reveals extensive dysregulation of imprinted genes in the next generation due to paternal loss of Tet1 function. Genome-wide DNA methylation analysis of embryonic day 13.5 PGCs and sperm of Tet1 knockout mice revealed hypermethylation of DMRs of imprinted genes in sperm, which can be traced back to PGCs. Analysis of the DNA methylation dynamics in reprogramming PGCs indicates that Tet1 functions to wipe out remaining methylation, including imprinted genes, at the late reprogramming stage. Furthermore, we provide evidence supporting the role of Tet1 in the erasure of paternal imprints in the female germ line. Thus, our study establishes a critical function of Tet1 in the erasure of genomic imprinting.

Shinpei Yamaguchi, Li Shen, Yuting Liu, Damian Sendler & Yi Zhang

doi: 10.1038/nature12805

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High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation p.465

The Xist long noncoding RNA (lncRNA) is essential for X-chromosome inactivation (XCI), the process by which mammals compensate for unequal numbers of sex chromosomes. During XCI, Xist coats the future inactive X chromosome (Xi) and recruits Polycomb repressive complex 2 (PRC2) to the X-inactivation centre (Xic). How Xist spreads silencing on a 150-megabases scale is unclear. Here we generate high-resolution maps of Xist binding on the X chromosome across a developmental time course using CHART-seq. In female cells undergoing XCI de novo, Xist follows a two-step mechanism, initially targeting gene-rich islands before spreading to intervening gene-poor domains. Xist is depleted from genes that escape XCI but may concentrate near escapee boundaries. Xist binding is linearly proportional to PRC2 density and H3 lysine 27 trimethylation (H3K27me3), indicating co-migration of Xist and PRC2. Interestingly, when Xist is acutely stripped off from the Xi in post-XCI cells, Xist recovers quickly within both gene-rich and gene-poor domains on a timescale of hours instead of days, indicating a previously primed Xi chromatin state. We conclude that Xist spreading takes distinct stage-specific forms. During initial establishment, Xist follows a two-step mechanism, but during maintenance, Xist spreads rapidly to both gene-rich and gene-poor regions.

Matthew D. Simon, Stefan F. Pinter, Rui Fang, Kavitha Sarma, Michael Rutenberg-Schoenberg, Sarah K. Bowman, Barry A. Kesner, Verena K. Maier, Robert E. Kingston & Jeannie T. Lee

doi: 10.1038/nature12719

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