Making the paper: Juan Carlos Izpisúa Belmonte

Nature 460, 9 (2009). doi:10.1038/7251009a

Healthy cells derived from diseased ones offer treatment hope.

Nature 460, 9 (2009). doi:10.1038/7251009b

First authorHave you ever noticed that when you buy, say, a red convertible, every other car on the road suddenly seems to be a red convertible? According to findings by Marius Peelen and his colleagues in the psychology department of Princeton University in New

Nature 460, 9 (2009). doi:10.1038/7251009c

Throw away those chemistry lab-course 'cookbooks', says Aaron Finke, guest blogger at The Sceptical Chymist (http://tinyurl.com/lvjw5q).A graduate student in organic chemistry at the University of Illinois in Urbana-Champaign, Finke recently oversaw an organic chemistry lab course attended primarily by students aiming to

Nature 460, 11 (2009). doi:10.1038/460011a

Iran's endogenous civil-rights movement needs international solidarity, not political meddling. Academics, universities and non-governmental organizations can help.

Nature 460, 12 (2009). doi:10.1038/460012a

Carbon dioxide is not the only warming agent worth tackling now in the bid to cool the planet.

Nature 460, 14 (2009). doi:10.1038/460014a

Nature Geosci.2, 488–491 (2009) 10.1038/ngeo553The Mississippi Delta is sinking, and to rebuild it some have proposed diverting the Mississippi River to carry sediment to coastal areas. But a new study shows that the delta's rivers don't have

Nature 460, 14 (2009). doi:10.1038/460014b

Science324, 1713–1716 (2009) 10.1126/science.1171721A protein associated with some cancers acts in the energy-producing organelles of the cell called mitochondria.The protein, STAT3, regulates gene expression. It is activated by the addition of a phosphate group, which sends

Nature 460, 15 (2009). doi:10.1038/460015c

Astrophys. J.699, 649–666 (2009) 10.1088/0004-637X/699/1/649How does one find dwarves in a crowd of giants? Evgenya Shkolnik at the Carnegie Institution of Washington in Washington DC and her colleagues searched X-ray data gathered by the now-defunct German satellite

Nature 460, 33 (2009). doi:10.1038/460033a

Authors: Lena Chan & Ahmed Djoghlaf

SirIn 2002 the World Summit on Sustainable Development assigned to the Convention on Biological Diversity (CBD) a target for 2010 of significantly reducing the rate of biodiversity loss. If we hope to chart positive trends in biodiversity conservation, then cities must now make a

Nature 460, 33 (2009). doi:10.1038/460033b

Authors: Christopher Thomas Scott, Jason Owen-Smith & Jennifer McCormick

SirYour Editorial 'Stem-cell clarity' (Nature459, 615–616; 10.1038/459615b2009) calls for reason in deliberations by the US National Institutes of Health (NIH) on public comments about proposed NIH guidelines for stem-cell research. We agree that rules barring the

Nature 460, 33 (2009). doi:10.1038/460033c

Author: François Diederich

SirI am shocked to read in Nature News online that the American Chemical Society intends to stop all personal subscriptions to its printed journals by 2010, and to start introducing major changes this year ('Chemistry publisher moving towards online-only journals' http://tinyurl.com/llae53).The

Nature 460, 34 (2009). doi:10.1038/460034a

Author: Peter Gill

The science of DNA profiling is firm, but the way that the adversarial justice system interprets probability can cause controversy, argues Peter Gill.

Nature 460, 35 (2009). doi:10.1038/460035a

Author: Eric Werner

A central question in biology is how multicellular organisms develop from a single cell and how development is controlled. The standard view is that the process is deterministic, following directives governed by information located in the genome. Molecular biologist Jean-Jacques Kupiec contradicts this picture. In

Nature 460, 36 (2009). doi:10.1038/460036a

Author: Josie Glausiusz

Roll up, roll up! See the giant Indricotherium, a plant-eating mammal from Mongolia that weighed as much as four adult African elephants! Gaze at the tiny bumblebee bat, which can hover in place like a hummingbird! Marvel at the wide-eyed sugar gliders, sailing nimbly

Nature 460, 37 (2009). doi:10.1038/460037a

Author: Colin Martin

Characterized by sinuous shapes and subtle colours, the glass vases, bowls and other objects made by the nineteenth-century French artist-designer Emile Gallé and his factory are still highly regarded. But his interest in botany and evolution is less well known. An exhibition this summer in

Nature 460, 39 (2009). doi:10.1038/460039a

Authors: Alejandro Sánchez Alvarado

How the salamander regrows an entire limb after injury has flummoxed the wisest of scientists. A closer look at the cells involved in limb regeneration shows that remembering past origins may be crucial for this feat.

Nature 460, 40 (2009). doi:10.1038/460040a

Authors: Yves Goddéris & Yannick Donnadieu

Levels of atmospheric carbon dioxide constrain vegetation types and thus also non-biological uptake during rock weathering. That's the reasoning used to explain why CO2 levels did not fall below a certain point in the Miocene.

Nature 460, 41 (2009). doi:10.1038/460041a

Authors: Martin Prlic & Michael J. Bevan

Two therapeutic drugs have been found to enhance memory in immune cells called T cells, apparently by altering cellular metabolism. Are changes in T-cell metabolism the key to generating long-lived immune memory?

Nature 460, 42 (2009). doi:10.1038/460042a

Authors: Michel Orrit

Photons don't interact well with each other, which is a real headache for researchers developing all-optical transistors for computing applications. But a single molecule can mediate photon–photon affairs.

Nature 460, 44 (2009). doi:10.1038/460044a

Authors: Sarah E. Millar

Actively dividing cells do so at a risk — with each division, chromosome ends tend to shorten. Pairing proteins that promote cell division with a chromosome-end repair factor is a smart way to solve this problem.

Nature 460, 45 (2009). doi:10.1038/460045a

Authors: Pavlo Zubko & Jean-Marc Triscone

As capacitors, the ubiquitous components of electronic circuitry, get smaller, keeping them insulating is a challenge. But that's not necessarily bad news — some conductivity might be just the thing for data storage.

Nature 460, 47 (2009). doi:10.1038/460047a

Authors: Solomon H. Snyder

Nobel laureate who pioneered research into nitric oxide.

Nature 460, 49 (2009). doi:10.1038/nature08180

Authors: Shinya Yamanaka

Induced pluripotent stem cells offer unprecedented potential for disease research, drug screening, toxicology and regenerative medicine. However, the process of reprogramming is inefficient and often incomplete. Here I consider reasons for bottlenecks in induced pluripotent stem cell generation, and propose a model in which most or all cells have the potential to become pluripotent.

Nature 460, 53 (2009). doi:10.1038/nature08129

Authors: Ángel Raya, Ignasi Rodríguez-Pizà, Guillermo Guenechea, Rita Vassena, Susana Navarro, María José Barrero, Antonella Consiglio, Maria Castellà, Paula Río, Eduard Sleep, Federico González, Gustavo Tiscornia, Elena Garreta, Trond Aasen, Anna Veiga, Inder M. Verma, Jordi Surrallés, Juan Bueren & Juan Carlos Izpisúa Belmonte

The generation of induced pluripotent stem (iPS) cells has enabled the derivation of patient-specific pluripotent cells and provided valuable experimental platforms to model human disease. Patient-specific iPS cells are also thought to hold great therapeutic potential, although direct evidence for this is still lacking. Here

Nature 460, 60 (2009). doi:10.1038/nature08152

Authors: Martin Kragl, Dunja Knapp, Eugen Nacu, Shahryar Khattak, Malcolm Maden, Hans Henning Epperlein & Elly M. Tanaka

During limb regeneration adult tissue is converted into a zone of undifferentiated progenitors called the blastema that reforms the diverse tissues of the limb. Previous experiments have led to wide acceptance that limb tissues dedifferentiate to form pluripotent cells. Here we have reexamined this question

Nature 460, 66 (2009). doi:10.1038/nature08137

Authors: Jae-Il Park, Andrew S. Venteicher, Ji Yeon Hong, Jinkuk Choi, Sohee Jun, Marina Shkreli, Woody Chang, Zhaojing Meng, Peggie Cheung, Hong Ji, Margaret McLaughlin, Timothy D. Veenstra, Roel Nusse, Pierre D. McCrea & Steven E. Artandi

Stem cells are controlled, in part, by genetic pathways frequently dysregulated during human tumorigenesis. Either stimulation of Wnt/β-catenin signalling or overexpression of telomerase is sufficient to activate quiescent epidermal stem cells in vivo, although the mechanisms by which telomerase exerts these effects are not

Nature 460, 73 (2009). doi:10.1038/nature08083

Authors: Sean A. Farrell, Natalie A. Webb, Didier Barret, Olivier Godet & Joana M. Rodrigues

Ultraluminous X-ray sources are extragalactic objects located outside the nucleus of the host galaxy with bolometric luminosities exceeding 1039 erg s-1. These extreme luminosities—if the emission is isotropic and below the theoretical (Eddington) limit, where the radiation pressure is balanced by the gravitational pressure—imply the presence of an accreting black hole with a mass of ∼102–105 solar masses (nature08083-m13jpg6163019). The existence of such intermediate-mass black holes is in dispute, and though many candidates have been proposed, none are widely accepted as definitive. Here we report the detection of a variable X-ray source with a maximum 0.2–10 keV luminosity of up to 1.1 × 1042 erg s-1 in the edge-on spiral galaxy ESO 243-49, with an implied conservative lower limit for the mass of the black hole of ∼500nature08083-m13jpg6163019.

Nature 460, 76 (2009). doi:10.1038/nature08134

Authors: J. Hwang, M. Pototschnig, R. Lettow, G. Zumofen, A. Renn, S. Götzinger & V. Sandoghdar

The transistor is one of the most influential inventions of modern times and is ubiquitous in present-day technologies. In the continuing development of increasingly powerful computers as well as alternative technologies based on the prospects of quantum information processing, switching and amplification functionalities are being sought in ultrasmall objects, such as nanotubes, molecules or atoms. Among the possible choices of signal carriers, photons are particularly attractive because of their robustness against decoherence, but their control at the nanometre scale poses a significant challenge as conventional nonlinear materials become ineffective. To remedy this shortcoming, resonances in optical emitters can be exploited, and atomic ensembles have been successfully used to mediate weak light beams. However, single-emitter manipulation of photonic signals has remained elusive and has only been studied in high-finesse microcavities or waveguides. Here we demonstrate that a single dye molecule can operate as an optical transistor and coherently attenuate or amplify a tightly focused laser beam, depending on the power of a second ‘gating’ beam that controls the degree of population inversion. Such a quantum optical transistor has also the potential for manipulating non-classical light fields down to the single-photon level. We discuss some of the hurdles along the road towards practical implementations, and their possible solutions.

Nature 460, 81 (2009). doi:10.1038/nature08128

Authors: V. Garcia, S. Fusil, K. Bouzehouane, S. Enouz-Vedrenne, N. D. Mathur, A. Barthélémy & M. Bibes

Ferroelectrics possess a polarization that is spontaneous, stable and electrically switchable, and submicrometre-thick ferroelectric films are currently used as non-volatile memory elements with destructive capacitive readout. Memories based on tunnel junctions with ultrathin ferroelectric barriers would enable non-destructive resistive readout. However, the achievement of room-temperature polarization stability and switching at very low thickness is challenging. Here we use piezoresponse force microscopy at room temperature to show robust ferroelectricity down to 1 nm in highly strained BaTiO3 films; we also use room-temperature conductive-tip atomic force microscopy to demonstrate resistive readout of the polarization state through its influence on the tunnel current. The resulting electroresistance effect scales exponentially with ferroelectric film thickness, reaching ∼75,000% at 3 nm. Our approach exploits the otherwise undesirable leakage current—dominated by tunnelling at these very low thicknesses—to read the polarization state without destroying it. We demonstrate scalability down to 70 nm, corresponding to potential densities of >16 Gbit inch-2. These results pave the way towards ferroelectric memories with simplified architectures, higher densities and faster operation, and should inspire further exploration of the interplay between quantum tunnelling and ferroelectricity at the nanoscale.

Nature 460, 85 (2009). doi:10.1038/nature08133

Authors: Mark Pagani, Ken Caldeira, Robert Berner & David J. Beerling

Environmental conditions during the past 24 million years are thought to have been favourable for enhanced rates of atmospheric carbon dioxide drawdown by silicate chemical weathering. Proxy records indicate, however, that the Earth’s atmospheric carbon dioxide concentrations did not fall below about 200–250 parts per million during this period. The stabilization of atmospheric carbon dioxide concentrations near this minimum value suggests that strong negative feedback mechanisms inhibited further drawdown of atmospheric carbon dioxide by high rates of global silicate rock weathering. Here we investigate one possible negative feedback mechanism, occurring under relatively low carbon dioxide concentrations and in warm climates, that is related to terrestrial plant productivity and its role in the decomposition of silicate minerals. We use simulations of terrestrial and geochemical carbon cycles and available experimental evidence to show that vegetation activity in upland regions of active orogens was severely limited by near-starvation of carbon dioxide in combination with global warmth over this period. These conditions diminished biotic-driven silicate rock weathering and thereby attenuated an important long-term carbon dioxide sink. Although our modelling results are semi-quantitative and do not capture the full range of biogeochemical feedbacks that could influence the climate, our analysis indicates that the dynamic equilibrium between plants, climate and the geosphere probably buffered the minimum atmospheric carbon dioxide concentrations over the past 24 million years.

Nature 460, 89 (2009). doi:10.1038/nature08095

Authors: J. Pablo Canales, Mladen R. Nedimović, Graham M. Kent, Suzanne M. Carbotte & Robert S. Detrick

The oceanic crust extends over two-thirds of the Earth’s solid surface, and is generated along mid-ocean ridges from melts derived from the upwelling mantle. The upper and middle crust are constructed by dyking and sea-floor eruptions originating from magma accumulated in mid-crustal lenses at the spreading axis, but the style of accretion of the lower oceanic crust is actively debated. Models based on geological and petrological data from ophiolites propose that the lower oceanic crust is accreted from melt sills intruded at multiple levels between the Moho transition zone (MTZ) and the mid-crustal lens, consistent with geophysical studies that suggest the presence of melt within the lower crust. However, seismic images of molten sills within the lower crust have been elusive. Until now, only seismic reflections from mid-crustal melt lenses and sills within the MTZ have been described, suggesting that melt is efficiently transported through the lower crust. Here we report deep crustal seismic reflections off the southern Juan de Fuca ridge that we interpret as originating from a molten sill at present accreting the lower oceanic crust. The sill sits 5–6 km beneath the sea floor and 850–900 m above the MTZ, and is located 1.4–3.2 km off the spreading axis. Our results provide evidence for the existence of low-permeability barriers to melt migration within the lower section of modern oceanic crust forming at intermediate-to-fast spreading rates, as inferred from ophiolite studies.

Nature 460, 94 (2009). doi:10.1038/nature08103

Authors: Marius V. Peelen, Li Fei-Fei & Sabine Kastner

The visual system has an extraordinary capability to extract categorical information from complex natural scenes. For example, subjects are able to rapidly detect the presence of object categories such as animals or vehicles in new scenes that are presented very briefly. This is even true when subjects do not pay attention to the scenes and simultaneously perform an unrelated attentionally demanding task, a stark contrast to the capacity limitations predicted by most theories of visual attention. Here we show a neural basis for rapid natural scene categorization in the visual cortex, using functional magnetic resonance imaging and an object categorization task in which subjects detected the presence of people or cars in briefly presented natural scenes. The multi-voxel pattern of neural activity in the object-selective cortex evoked by the natural scenes contained information about the presence of the target category, even when the scenes were task-irrelevant and presented outside the focus of spatial attention. These findings indicate that the rapid detection of categorical information in natural scenes is mediated by a category-specific biasing mechanism in object-selective cortex that operates in parallel across the visual field, and biases information processing in favour of objects belonging to the target object category.

Nature 460, 98 (2009). doi:10.1038/nature08123

Authors: Nisheeth Agarwal, Gyanu Lamichhane, Radhika Gupta, Scott Nolan & William R. Bishai

With 8.9 million new cases and 1.7 million deaths per year, tuberculosis is a leading global killer that has not been effectively controlled. The causative agent, Mycobacterium tuberculosis, proliferates within host macrophages where it modifies both its intracellular and local tissue environment, resulting in caseous granulomas with incomplete bacterial sterilization. Although infection by various mycobacterial species produces a cyclic AMP burst within macrophages that influences cell signalling, the underlying mechanism for the cAMP burst remains unclear. Here we show that among the 17 adenylate cyclase genes present in M. tuberculosis, at least one (Rv0386) is required for virulence. Furthermore, we demonstrate that the Rv0386 adenylate cyclase facilitates delivery of bacterial-derived cAMP into the macrophage cytoplasm. Loss of Rv0386 and the intramacrophage cAMP it delivers results in reductions in TNF-α production via the protein kinase A and cAMP response-element-binding protein pathway, decreased immunopathology in animal tissues, and diminished bacterial survival. Direct intoxication of host cells by bacterial-derived cAMP may enable M. tuberculosis to modify both its intracellular and tissue environments to facilitate its long-term survival.

Nature 460, 103 (2009). doi:10.1038/nature08097

Authors: Erika L. Pearce, Matthew C. Walsh, Pedro J. Cejas, Gretchen M. Harms, Hao Shen, Li-San Wang, Russell G. Jones & Yongwon Choi

CD8 T cells, which have a crucial role in immunity to infection and cancer, are maintained in constant numbers, but on antigen stimulation undergo a developmental program characterized by distinct phases encompassing the expansion and then contraction of antigen-specific effector (TE) populations, followed by the persistence of long-lived memory (TM) cells. Although this predictable pattern of CD8 T-cell responses is well established, the underlying cellular mechanisms regulating the transition to TM cells remain undefined. Here we show that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an adaptor protein in the TNF-receptor and interleukin-1R/Toll-like receptor superfamily, regulates CD8 TM-cell development after infection by modulating fatty acid metabolism. We show that mice with a T-cell-specific deletion of TRAF6 mount robust CD8 TE-cell responses, but have a profound defect in their ability to generate TM cells that is characterized by the disappearance of antigen-specific cells in the weeks after primary immunization. Microarray analyses revealed that TRAF6-deficient CD8 T cells exhibit altered expression of genes that regulate fatty acid metabolism. Consistent with this, activated CD8 T cells lacking TRAF6 display defective AMP-activated kinase activation and mitochondrial fatty acid oxidation (FAO) in response to growth factor withdrawal. Administration of the anti-diabetic drug metformin restored FAO and CD8 TM-cell generation in the absence of TRAF6. This treatment also increased CD8 TM cells in wild-type mice, and consequently was able to considerably improve the efficacy of an experimental anti-cancer vaccine.

Nature 460, 108 (2009). doi:10.1038/nature08155

Authors: Koichi Araki, Alexandra P. Turner, Virginia Oliva Shaffer, Shivaprakash Gangappa, Susanne A. Keller, Martin F. Bachmann, Christian P. Larsen & Rafi Ahmed

Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. Here we show that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced not only the quantity but also the quality of virus-specific CD8 T cells. Similar effects were seen after immunization of mice with a vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with modified vaccinia virus Ankara. Rapamycin was effective during both the expansion and contraction phases of the T-cell response; during the expansion phase it increased the number of memory precursors, and during the contraction phase (effector to memory transition) it accelerated the memory T-cell differentiation program. Experiments using RNA interference to inhibit expression of mTOR, raptor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 (mTOR complex 1) pathway to regulate memory T-cell differentiation. Thus these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine- or infection-induced memory T cells.

Nature 460, 113 (2009). doi:10.1038/nature08191

Authors: Lei Bu, Xin Jiang, Silvia Martin-Puig, Leslie Caron, Shenjun Zhu, Ying Shao, Drucilla J. Roberts, Paul L. Huang, Ibrahim J. Domian & Kenneth R. Chien

The generation and expansion of diverse cardiovascular cell lineages is a critical step during human cardiogenesis, with major implications for congenital heart disease. Unravelling the mechanisms for the diversification of human heart cell lineages has been hampered by the lack of genetic tools to purify early cardiac progenitors and define their developmental potential. Recent studies in the mouse embryo have identified a multipotent cardiac progenitor that contributes to all of the major cell types in the murine heart. In contrast to murine development, human cardiogenesis has a much longer onset of heart cell lineage diversification and expansion, suggesting divergent pathways. Here we identify a diverse set of human fetal ISL1+ cardiovascular progenitors that give rise to the cardiomyocyte, smooth muscle and endothelial cell lineages. Using two independent transgenic and gene-targeting approaches in human embryonic stem cell lines, we show that purified ISL1+ primordial progenitors are capable of self-renewal and expansion before differentiation into the three major cell types in the heart. These results lay the foundation for the generation of human model systems for cardiovascular disease and novel approaches for human regenerative cardiovascular medicine.

Nature 460, 118 (2009). doi:10.1038/nature08113

Authors: Hitoshi Niwa, Kazuya Ogawa, Daisuke Shimosato & Kenjiro Adachi

The cytokine leukaemia inhibitory factor (LIF) integrates signals into mouse embryonic stem (ES) cells to maintain pluripotency. Although the Jak–Stat3 pathway is essential and sufficient to mediate LIF signals, it is still unclear how these signals are linked to the core circuitry of pluripotency-associated transcription factors, consisting of Oct3/4 (also called Pou5f1), Sox2 and Nanog. Here we show that two LIF signalling pathways are each connected to the core circuitry via different transcription factors. In mouse ES cells, Klf4 is mainly activated by the Jak–Stat3 pathway and preferentially activates Sox2, whereas Tbx3 is preferentially regulated by the phosphatidylinositol-3-OH kinase–Akt and mitogen-activated protein kinase pathways and predominantly stimulates Nanog. In the absence of LIF, artificial expression of Klf4 or Tbx3 is sufficient to maintain pluripotency while maintaining the expression of Oct3/4. Notably, overexpression of Nanog supports LIF-independent self-renewal of mouse ES cells in the absence of Klf4 and Tbx3 activity. Therefore, Klf4 and Tbx3 are involved in mediating LIF signalling to the core circuitry but are not directly associated with the maintenance of pluripotency, because ES cells keep pluripotency without their expression in the particular context.

Nature 460, 123 (2009). doi:10.1038/nature08087

Authors: Su Kit Chew, Po Chen, Nichole Link, Kathleen A. Galindo, Kristi Pogue & John M. Abrams

Apoptosis is a conserved form of programmed cell death firmly established in the aetiology, pathogenesis and treatment of many human diseases. Central to the core machinery of apoptosis are the caspases and their proximal regulators. Current models for caspase control involve a balance of opposing elements, with variable contributions from positive and negative regulators among different cell types and species. To advance a comprehensive view of components that support caspase-dependent cell death, we conducted a genome-wide silencing screen in the Drosophila model. Our strategy used a library of double-stranded RNAs together with a chemical antagonist of Inhibitor of apoptosis proteins (IAPs) that simulates the action of native regulators in the Reaper and Smac (also known as Diablo) families. Here we present a highly validated set of targets that is necessary for death provoked by several stimuli. Among these, Tango7 is identified as a new effector. Cells depleted for this gene resisted apoptosis at a step before the induction of effector caspase activity, and the directed silencing of Tango7 in Drosophila prevented caspase-dependent programmed cell death. Unlike known apoptosis regulators in this model system, Tango7 activity did not influence stimulus-dependent loss of Drosophila DIAP1 (also known as th and IAP1), but instead regulated levels of the apical caspase Dronc (Nc). Similarly, the human Tango7 counterpart, PCID1 (also known as EIF3M), impinged on caspase 9, revealing a new regulatory axis affecting the apoptosome.

Nature 460, 128 (2009). doi:10.1038/nature08098

Authors: Mary E. Donohoe, Susana S. Silva, Stefan F. Pinter, Na Xu & Jeannie T. Lee

Pluripotency of embryonic stem (ES) cells is controlled by defined transcription factors. During differentiation, mouse ES cells undergo global epigenetic reprogramming, as exemplified by X-chromosome inactivation (XCI) in which one female X chromosome is silenced to achieve gene dosage parity between the sexes. Somatic XCI is regulated by homologous X-chromosome pairing and counting, and by the random choice of future active and inactive X chromosomes. XCI and cell differentiation are tightly coupled, as blocking one process compromises the other and dedifferentiation of somatic cells to induced pluripotent stem cells is accompanied by X chromosome reactivation. Recent evidence suggests coupling of Xist expression to pluripotency factors occurs, but how the two are interconnected remains unknown. Here we show that Oct4 (also known as Pou5f1) lies at the top of the XCI hierarchy, and regulates XCI by triggering X-chromosome pairing and counting. Oct4 directly binds Tsix and Xite, two regulatory noncoding RNA genes of the X-inactivation centre, and also complexes with XCI trans-factors, Ctcf and Yy1 (ref. 17), through protein–protein interactions. Depletion of Oct4 blocks homologous X-chromosome pairing and results in the inactivation of both X chromosomes in female cells. Thus, we have identified the first trans-factor that regulates counting, and ascribed new functions to Oct4 during X-chromosome reprogramming.

Nature 460, 140 (2009). doi:10.1038/460140a

Author: Janett L. Grady

All play and no work is a recipe for disaster.