네이처 컨텐츠

Editorials

What lies beneath p.273

A focus on specific biological targets rather than constellations of symptoms heralds a more scientific approach to the treatment of neuropsychiatric disorders.

doi: 10.1038/507273a

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How to get ahead p.273

The success of the $1,000 genome programme offers lessons for fostering innovation.

doi: 10.1038/507273b

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Past wisdom p.274

The recent Nature PastCast series is instructive as well as entertaining.

doi: 10.1038/507274a

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News

NIH rethinks psychiatry trials p.288

Mental-health division will no longer fund research aiming to relieve symptoms without probing underlying causes.

Sara Reardon

doi: 10.1038/507288a

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News Features

Tuning the brain p.290

Deep brain stimulation has shown promise in treating conditions such as Parkinson's disease. Now scientists are using the technology to eavesdrop on problem neural circuits.

Helen Shen

doi: 10.1038/507290a

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The $1,000 genome p.294

With a unique programme, the US government has managed to drive the cost of genome sequencing down towards a much-anticipated target.

Erika Check Hayden

doi: 10.1038/507294a

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News & Views

Near-Earth space shows its stripes p.308

Electrons in Earth's magnetic field often exhibit a striped pattern of intensity as a function of electron energy and altitude. A model that factors in some unexpectedly important effects can now explain this feature. See Letter p.338

Drew L. Turner

doi: 10.1038/507308a

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Closing the distance on obesity culprits p.309

Genetic variation in a non-protein-coding region of the gene FTO is implicated in obesity. A study finds evidence that, rather than affecting FTO itself, variations in this region influence expression of a distant gene, IRX3. See Letter p.371

David U. Gorkin & Bing Ren

doi: 10.1038/nature13212

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Photonics illuminates the future of radar p.310

The first implementation of a fully photonics-based coherent radar system shows how photonic methods for radio-frequency signal generation and measurement may facilitate the development of software-defined radar systems. See Letter p.341

Jason D. McKinney

doi: 10.1038/507310a

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The disassembly of death p.312

During the cell-death program known as apoptosis, cells break up into membrane-bound fragments. It emerges that this process is controlled by the protein pannexin 1 and can be deregulated by an antibiotic. See Article p.329

Christopher D. Gregory

doi: 10.1038/nature13213

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Vessels of rejuvenation p.313

The identification of specialized endothelial-cell populations in the blood vessels of bones, and their signalling pathways, reveals how the vasculature contributes to bone formation. See Article p.323 & Letter p.376

Ferdinand le Noble & Jos le Noble

doi: 10.1038/nature13210

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Articles

Comprehensive molecular characterization of urothelial bladder carcinoma OPEN p.315

This paper reports integrative molecular analyses of urothelial bladder carcinoma at the DNA, RNA, and protein levels performed as part of The Cancer Genome Atlas project; recurrent mutations were found in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways; chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far.

doi: 10.1038/nature12965

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Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone p.323

Bone homeostasis and repair declines with ageing and the mechanisms regulating the relationship between bone growth and blood vessel formation have remained unknown; this mouse study identifies the endothelial cells that promote the formation of new bone, a small microvessel subtype that can be identified by high CD31 and high Emcn expression.

Anjali P. Kusumbe, Saravana K. Ramasamy & Ralf H. Adams

doi: 10.1038/nature13145

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Unexpected link between an antibiotic, pannexin channels and apoptosis p.329

The pannexin 1 channel on the plasma membrane of apoptotic cells mediates the release of find-me molecular signals to attract phagocytic cells for clearance of the apoptotic cells; here the quinolone antibiotic trovafloxacin is identified as a direct inhibitor of pannexin 1, which results in dysregulated fragmentation of apoptotic cells and may partly explain quinolone toxicity.

Ivan K. H. Poon, Yu-Hsin Chiu, Allison J. Armstrong, Jason M. Kinchen, Ignacio J. Juncadella, Douglas A. Bayliss & Kodi S. Ravichandran

doi: 10.1038/nature13147

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Letters

The remnant of a merger between two dwarf galaxies in Andromeda II p.335

Driven by gravity, massive structures like galaxies and clusters of galaxies are believed to grow continuously through hierarchical merging and accretion of smaller systems. Observational evidence of accretion events is provided by the coherent stellar streams crossing the outer haloes of massive galaxies, such as the Milky Way or Andromeda. At similar mass scales, around 1011 solar masses in stars, further evidence of merging activity is also ample. Mergers of lower-mass galaxies are expected within the hierarchical process of galaxy formation, but have hitherto not been seen for galaxies with less than about 109 solar masses in stars. Here we report the kinematic detection of a stellar stream in one of the satellite galaxies of Andromeda, the dwarf spheroidal Andromeda II, which has a mass of only 107 solar masses in stars. The properties of the stream show that we are observing the remnant of a merger between two dwarf galaxies. This had a drastic influence on the dynamics of the remnant, which is now rotating around its projected major axis. The stellar stream in Andromeda II illustrates the scale-free character of the formation of galaxies, down to the lowest galactic mass scales.

N. C. Amorisco, N. W. Evans & G. van de Ven

doi: 10.1038/nature12995

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Rotationally driven ‘zebra stripes’ in Earth’s inner radiation belt p.338

Structured features on top of nominally smooth distributions of radiation-belt particles at Earth have been previously associated with particle acceleration and transport mechanisms powered exclusively by enhanced solar-wind activity. Although planetary rotation is considered to be important for particle acceleration at Jupiter and Saturn, the electric field produced in the inner magnetosphere by Earth’s rotation can change the velocity of trapped particles by only about 1–2 kilometres per second, so rotation has been thought inconsequential for radiation-belt electrons with velocities of about 100,000 kilometres per second. Here we report that the distributions of energetic electrons across the entire spatial extent of Earth’s inner radiation belt are organized in regular, highly structured and unexpected ‘zebra stripes’, even when the solar-wind activity is low. Modelling reveals that the patterns are produced by Earth’s rotation. Radiation-belt electrons are trapped in Earth’s dipole-like magnetic field, where they undergo slow longitudinal drift motion around the planet because of the gradient and curvature of the magnetic field. Earth’s rotation induces global diurnal variations of magnetic and electric fields that resonantly interact with electrons whose drift period is close to 24 hours, modifying electron fluxes over a broad energy range into regular patterns composed of multiple stripes extending over the entire span of the inner radiation belt.

A. Y. Ukhorskiy, M. I. Sitnov, D. G. Mitchell, K. Takahashi, L. J. Lanzerotti & B. H. Mauk

doi: 10.1038/nature13046

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A fully photonics-based coherent radar system p.341

The next generation of radar (radio detection and ranging) systems needs to be based on software-defined radio to adapt to variable environments, with higher carrier frequencies for smaller antennas and broadened bandwidth for increased resolution. Today’s digital microwave components (synthesizers and analogue-to-digital converters) suffer from limited bandwidth with high noise at increasing frequencies, so that fully digital radar systems can work up to only a few gigahertz, and noisy analogue up- and downconversions are necessary for higher frequencies. In contrast, photonics provide high precision and ultrawide bandwidth, allowing both the flexible generation of extremely stable radio-frequency signals with arbitrary waveforms up to millimetre waves, and the detection of such signals and their precise direct digitization without downconversion. Until now, the photonics-based generation and detection of radio-frequency signals have been studied separately and have not been tested in a radar system. Here we present the development and the field trial results of a fully photonics-based coherent radar demonstrator carried out within the project PHODIR. The proposed architecture exploits a single pulsed laser for generating tunable radar signals and receiving their echoes, avoiding radio-frequency up- and downconversion and guaranteeing both the software-defined approach and high resolution. Its performance exceeds state-of-the-art electronics at carrier frequencies above two gigahertz, and the detection of non-cooperating aeroplanes confirms the effectiveness and expected precision of the system.

Paolo Ghelfi, Francesco Laghezza, Filippo Scotti, Giovanni Serafino, Amerigo Capria, Sergio Pinna, Daniel Onori, Claudio Porzi, Mirco Scaffardi, Antonio Malacarne + et al.

doi: 10.1038/nature13078

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Sulphide oxidation and carbonate dissolution as a source of CO2 over geological timescales p.346

The observed stability of Earth’s climate over millions of years is thought to depend on the rate of carbon dioxide (CO2) release from the solid Earth being balanced by the rate of CO2 consumption by silicate weathering. During the Cenozoic era, spanning approximately the past 66 million years, the concurrent increases in the marine isotopic ratios of strontium, osmium and lithium suggest that extensive uplift of mountain ranges may have stimulated CO2 consumption by silicate weathering, but reconstructions of sea-floor spreading do not indicate a corresponding increase in CO2 inputs from volcanic degassing. The resulting imbalance would have depleted the atmosphere of all CO2 within a few million years. As a result, reconciling Cenozoic isotopic records with the need for mass balance in the long-term carbon cycle has been a major and unresolved challenge in geochemistry and Earth history. Here we show that enhanced sulphide oxidation coupled to carbonate dissolution can provide a transient source of CO2 to Earth’s atmosphere that is relevant over geological timescales. Like drawdown by means of silicate weathering, this source is probably enhanced by tectonic uplift, and so may have contributed to the relative stability of the partial pressure of atmospheric CO2 during the Cenozoic. A variety of other hypotheses have been put forward to explain the ‘Cenozoic isotope-weathering paradox’, and the evolution of the carbon cycle probably depended on multiple processes. However, an important role for sulphide oxidation coupled to carbonate dissolution is consistent with records of radiogenic isotopes, atmospheric CO2 partial pressure and the evolution of the Cenozoic sulphur cycle, and could be accounted for by geologically reasonable changes in the global dioxygen cycle, suggesting that this CO2 source should be considered a potentially important but as yet generally unrecognized component of the long-term carbon cycle.

Mark A. Torres, A. Joshua West & Gaojun Li

doi: 10.1038/nature13030

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Melanosome evolution indicates a key physiological shift within feathered dinosaurs p.350

Inference of colour patterning in extinct dinosaurs has been based on the relationship between the morphology of melanin-containing organelles (melanosomes) and colour in extant bird feathers. When this relationship evolved relative to the origin of feathers and other novel integumentary structures, such as hair and filamentous body covering in extinct archosaurs, has not been evaluated. Here we sample melanosomes from the integument of 181 extant amniote taxa and 13 lizard, turtle, dinosaur and pterosaur fossils from the Upper-Jurassic and Lower-Cretaceous of China. We find that in the lineage leading to birds, the observed increase in the diversity of melanosome morphologies appears abruptly, near the origin of pinnate feathers in maniraptoran dinosaurs. Similarly, mammals show an increased diversity of melanosome form compared to all ectothermic amniotes. In these two clades, mammals and maniraptoran dinosaurs including birds, melanosome form and colour are linked and colour reconstruction may be possible. By contrast, melanosomes in lizard, turtle and crocodilian skin, as well as the archosaurian filamentous body coverings (dinosaur ‘protofeathers’ and pterosaur ‘pycnofibres’), show a limited diversity of form that is uncorrelated with colour in extant taxa. These patterns may be explained by convergent changes in the key melanocortin system of mammals and birds, which is known to affect pleiotropically both melanin-based colouration and energetic processes such as metabolic rate in vertebrates, and may therefore support a significant physiological shift in maniraptoran dinosaurs.

Quanguo Li, Julia A. Clarke, Ke-Qin Gao, Chang-Fu Zhou, Qingjin Meng, Daliang Li, Liliana D’Alba & Matthew D. Shawkey

doi: 10.1038/nature12973

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The genomic landscape of Neanderthal ancestry in present-day humans p.354

Genomic studies have shown that Neanderthals interbred with modern humans, and that non-Africans today are the products of this mixture. The antiquity of Neanderthal gene flow into modern humans means that genomic regions that derive from Neanderthals in any one human today are usually less than a hundred kilobases in size. However, Neanderthal haplotypes are also distinctive enough that several studies have been able to detect Neanderthal ancestry at specific loci. We systematically infer Neanderthal haplotypes in the genomes of 1,004 present-day humans. Regions that harbour a high frequency of Neanderthal alleles are enriched for genes affecting keratin filaments, suggesting that Neanderthal alleles may have helped modern humans to adapt to non-African environments. We identify multiple Neanderthal-derived alleles that confer risk for disease, suggesting that Neanderthal alleles continue to shape human biology. An unexpected finding is that regions with reduced Neanderthal ancestry are enriched in genes, implying selection to remove genetic material derived from Neanderthals. Genes that are more highly expressed in testes than in any other tissue are especially reduced in Neanderthal ancestry, and there is an approximately fivefold reduction of Neanderthal ancestry on the X chromosome, which is known from studies of diverse species to be especially dense in male hybrid sterility genes. These results suggest that part of the explanation for genomic regions of reduced Neanderthal ancestry is Neanderthal alleles that caused decreased fertility in males when moved to a modern human genetic background.

Sriram Sankararaman, Swapan Mallick, Michael Dannemann, Kay Prüfer, Janet Kelso, Svante Pääbo, Nick Patterson & David Reich

doi: 10.1038/nature12961

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A dedicated circuit links direction-selective retinal ganglion cells to the primary visual cortex p.358

How specific features in the environment are represented within the brain is an important unanswered question in neuroscience. A subset of retinal neurons, called direction-selective ganglion cells (DSGCs), are specialized for detecting motion along specific axes of the visual field. Despite extensive study of the retinal circuitry that endows DSGCs with their unique tuning properties, their downstream circuitry in the brain and thus their contribution to visual processing has remained unclear. In mice, several different types of DSGCs connect to the dorsal lateral geniculate nucleus (dLGN), the visual thalamic structure that harbours cortical relay neurons. Whether direction-selective information computed at the level of the retina is routed to cortical circuits and integrated with other visual channels, however, is unknown. Here we show that there is a di-synaptic circuit linking DSGCs with the superficial layers of the primary visual cortex (V1) by using viral trans-synaptic circuit mapping and functional imaging of visually driven calcium signals in thalamocortical axons. This circuit pools information from several types of DSGCs, converges in a specialized subdivision of the dLGN, and delivers direction-tuned and orientation-tuned signals to superficial V1. Notably, this circuit is anatomically segregated from the retino-geniculo-cortical pathway carrying non-direction-tuned visual information to deeper layers of V1, such as layer 4. Thus, the mouse harbours several functionally specialized, parallel retino-geniculo-cortical pathways, one of which originates with retinal DSGCs and delivers direction- and orientation-tuned information specifically to the superficial layers of the primary visual cortex. These data provide evidence that direction and orientation selectivity of some V1 neurons may be influenced by the activation of DSGCs.

Alberto Cruz-Martín, Rana N. El-Danaf, Fumitaka Osakada, Balaji Sriram, Onkar S. Dhande, Phong L. Nguyen, Edward M. Callaway, Anirvan Ghosh & Andrew D. Huberman

doi: 10.1038/nature12989

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Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo live imaging p.362

The rapid turnover of the mammalian intestinal epithelium is supported by stem cells located around the base of the crypt. In addition to the Lgr5 marker, intestinal stem cells have been associated with other markers that are expressed heterogeneously within the crypt base region. Previous quantitative clonal fate analyses have led to the proposal that homeostasis occurs as the consequence of neutral competition between dividing stem cells. However, the short-term behaviour of individual Lgr5+ cells positioned at different locations within the crypt base compartment has not been resolved. Here we establish the short-term dynamics of intestinal stem cells using the novel approach of continuous intravital imaging of Lgr5-Confetti mice. We find that Lgr5+ cells in the upper part of the niche (termed ‘border cells’) can be passively displaced into the transit-amplifying domain, after the division of proximate cells, implying that the determination of stem-cell fate can be uncoupled from division. Through quantitative analysis of individual clonal lineages, we show that stem cells at the crypt base, termed ‘central cells’, experience a survival advantage over border stem cells. However, through the transfer of stem cells between the border and central regions, all Lgr5+ cells are endowed with long-term self-renewal potential. These findings establish a novel paradigm for stem-cell maintenance in which a dynamically heterogeneous cell population is able to function long term as a single stem-cell pool.

Laila Ritsma, Saskia I. J. Ellenbroek, Anoek Zomer, Hugo J. Snippert, Frederic J. de Sauvage, Benjamin D. Simons, Hans Clevers & Jacco van Rheenen

doi: 10.1038/nature12972

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IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases p.366

B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM+CD138hiTACI+CXCR4+CD1dintTim1int plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138+ plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease.

Ping Shen, Toralf Roch, Vicky Lampropoulou, Richard A. O’Connor, Ulrik Stervbo, Ellen Hilgenberg, Stefanie Ries, Van Duc Dang, Yarúa Jaimes, Capucine Daridon + et al.

doi: 10.1038/nature12979

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Obesity-associated variants within FTO form long-range functional connections with IRX3 p.371

Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. However, no direct connection between the obesity-associated variants and FTO expression or function has been made. Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.

Scott Smemo, Juan J. Tena, Kyoung-Han Kim, Eric R. Gamazon, Noboru J. Sakabe, Carlos Gómez-Marín, Ivy Aneas, Flavia L. Credidio, Débora R. Sobreira, Nora F. Wasserman + et al.

doi: 10.1038/nature13138

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Endothelial Notch activity promotes angiogenesis and osteogenesis in bone p.376

Blood vessel growth in the skeletal system and osteogenesis seem to be coupled, suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells. Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here we show that vascular growth in bone involves a specialized, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours. Endothelial-cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. On the basis of a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralization, chondrocyte maturation, the formation of trabeculae and osteoprogenitor numbers in endothelial-cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications.

Saravana K. Ramasamy, Anjali P. Kusumbe, Lin Wang & Ralf H. Adams

doi: 10.1038/nature13146

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Two independent transcription initiation codes overlap on vertebrate core promoters p.381

A core promoter is a stretch of DNA surrounding the transcription start site (TSS) that integrates regulatory inputs and recruits general transcription factors to initiate transcription. The nature and causative relationship of the DNA sequence and chromatin signals that govern the selection of most TSSs by RNA polymerase II remain unresolved. Maternal to zygotic transition represents the most marked change of the transcriptome repertoire in the vertebrate life cycle. Early embryonic development in zebrafish is characterized by a series of transcriptionally silent cell cycles regulated by inherited maternal gene products: zygotic genome activation commences at the tenth cell cycle, marking the mid-blastula transition. This transition provides a unique opportunity to study the rules of TSS selection and the hierarchy of events linking transcription initiation with key chromatin modifications. We analysed TSS usage during zebrafish early embryonic development at high resolution using cap analysis of gene expression, and determined the positions of H3K4me3-marked promoter-associated nucleosomes. Here we show that the transition from the maternal to zygotic transcriptome is characterized by a switch between two fundamentally different modes of defining transcription initiation, which drive the dynamic change of TSS usage and promoter shape. A maternal-specific TSS selection, which requires an A/T-rich (W-box) motif, is replaced with a zygotic TSS selection grammar characterized by broader patterns of dinucleotide enrichments, precisely aligned with the first downstream (+1) nucleosome. The developmental dynamics of the H3K4me3-marked nucleosomes reveal their DNA-sequence-associated positioning at promoters before zygotic transcription and subsequent transcription-independent adjustment to the final position downstream of the zygotic TSS. The two TSS-defining grammars coexist, often physically overlapping, in core promoters of constitutively expressed genes to enable their expression in the two regulatory environments. The dissection of overlapping core promoter determinants represents a framework for future studies of promoter structure and function across different regulatory contexts.

Vanja Haberle, Nan Li, Yavor Hadzhiev, Charles Plessy, Christopher Previti, Chirag Nepal, Jochen Gehrig, Xianjun Dong, Altuna Akalin, Ana Maria Suzuki + et al.

doi: 10.1038/nature12974

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