2016-12-06Trials in animals can aid both veterinary and human medicine, but complicated rules can stifle them.
2016-12-07Human activity causes most changes in Earth’s surface water, so policies for its governance must become a priority.
2016-12-07Books have the power to trigger a lifelong urge to know more about the world and its environs.
2016-12-06Scientists should challenge online falsehoods and inaccuracies — and harness the collective power of the Internet to fight back, argues Phil Williamson.
2016-12-07Ancient humans in South America used complex funeral rituals and manipulated the bodies of their dead as early as 10,000 years ago.André Strauss at the University of Tübingen in Germany and his colleagues analysed bones from 26 human burials, discovered during 15 years of
2016-12-07Bismuth crystals can act as superconductors — but only at temperatures approaching absolute zero.Researchers have long been searching for new superconducting materials, which have the ability to maintain an electric current with no power source. A team led by Srinivasan Ramakrishnan at the Tata
2016-12-07A live, genetically modified flu virus can infect animals and trigger a strong immune response, but cannot multiply in its host's cells. Such modified viruses could one day be used to improve on current vaccines (pictured).Vaccines made of live viruses elicit stronger
2016-12-07Bacteria living in the gut may contribute to movement problems seen in disorders such as Parkinson's disease.Timothy Sampson and Sarkis Mazmanian at the California Institute of Technology in Pasadena and their team generated mice that lacked their own bacteria and had been genetically engineered
2016-12-07Cancer can return after seemingly successful treatment, and researchers have isolated a small population of dormant cancer cells that could cause this in a type of leukaemia.Irmela Jeremias at the Helmholtz Center Munich in Germany and her colleagues isolated tumour cells from people with
2016-12-07X-ray scans of the remains of a 3.2-million-year-old human relative known as Lucy suggest she was built for climbing trees.Members of Lucy's species, Australopithecus afarensis, walked upright, but researchers have long debated whether they routinely climbed trees. Christopher Ruff at Johns Hopkins University
2016-12-07As Earth emerged from the last ice age more than 10,000 years ago, West Antarctica (pictured) warmed two to three times faster than the rest of the planet.A team led by Kurt Cuffey at the University of California, Berkeley, measured temperatures along
2016-12-07Single light particles can be manipulated to form a mixture or 'superposition' of two colours at the same time.Quantum computing requires particles to be simultaneously in two quantum states, but the creation of two-colour photons requires individual light particles to interact, which they rarely
2016-12-07Mutations in a gene targeted by a new wave of medicines for lowering cholesterol levels may protect against heart attacks, but perhaps also increase the risk of diabetes.Drugs that inhibit a protein called PCSK9 lower cholesterol, but have not yet been shown definitively to
2016-12-07The week in science: 2–8 December 2016
2016-12-02But the European Space Agency's participation in a mission to deflect an asteroid moon is now cancelled.
2016-12-07DNA proves Native American roots of 10,600-year-old skeleton.
2016-12-07Researchers in the country have only just started using homegrown human embryonic stem cells
2016-12-01Institutions struggle to respond after court blocks regulations that would have increased wages for junior researchers.
2016-11-30Illegal land clearing hits highest levels since 2008 as environmental policies come under attack.
2016-12-06Economic woes wrought by globalization are only part of the cause.
2016-12-07Investigation of a 150-year-old burial site is helping to unlock the mysteries of one of humanity’s darkest chapters.
2016-12-05Better surveillance data and analyses are urgently needed to control disease in the developing world, argue Scott F. Dowell, David Blazes and Susan Desmond-Hellmann.
2016-12-07The causes of Earth's transition are human and social, write Erle Ellis and colleagues, so scholars from those disciplines must be included in its formalization.
2016-12-07A bedtime story can ignite a lifelong love of science. Nature editors riffle through shelves and memories for favourites old and new.
2016-12-07Brazil has reduced deforestation in the Amazon by almost 80%, a major contribution to the goals of the United Nations Convention on Biological Diversity (CBD). Neighbouring Cerrado, a vast tropical savannah that hosts some 4,800 species of plants and vertebrates found nowhere else, has not
2016-12-07Gino Segrè and Bettina Hoerlin's biography of Enrico Fermi — The Pope of Physics (Henry Holt, 2016) — is a delightful sequel to the inspiring Atoms in the Family, written by Fermi's wife Laura in 1954 (Univ. of Chicago Press). I find reviewer
2016-12-07The UK Biotechnology and Biological Sciences Research Council (BBSRC) surveyed more than 800 technicians and laboratory assistants about their roles, careers and professional recognition (see go.nature.com/2fs6icb). The results reveal opportunities for change in the current ill-defined status of technical staff.These non-faculty members professed
2016-12-07The question of which institutions produce the most Nobel prizewinners is one not just of numbers but of ratios (see Nature538, 152;10.1038/nature.2016.207572016). Merely counting doesn't cut it.We analysed the distribution of US Nobel laureates and members of the
2016-12-07As someone who once held the world's first laser in my hand (while interviewing its inventor, the late Ted Maiman), I find the expression 'laser-focused' irritating. That phrase, or the equally misleading 'focused like a laser', appears at least twice in Nature's 27 October
2016-12-07Nature announces this year's outstanding science mentors from the US west coast.
2016-12-07Steffen Schulz wanted high job security.
2016-12-07For centuries, scientists have been captivated by the phenomenal feats of regeneration found in nature. Despite decades of research, attempts to replace or repair parts of the human body have met with only modest success. Fresh understanding of organ formation coupled with new technologies may help to unlock long-sought cures.
2016-12-07Stem-cell therapy promises to restore motor function after a stroke or spinal-cord injury, but neurologists are proceeding with caution.
2016-12-07Advances in technology have outpaced our understanding of organ development and injury response. It's time to reassess, says Stephen Badylak.
2016-12-07Machines that deposit cell-laden inks are constructing tissues and organs, one layer at a time.
2016-12-07Some animals can regrow body parts with ease. Biologists hope to figure out their secrets and apply them to humans.
2016-12-07Cell therapy could cure type 1 diabetes — if only the immune system didn't get in the way.
2016-12-07In the story ‘Speedy drills start hunt for oldest ice’ (Nature540, 18–19; 2016), the size of the borehole to be drilled by the US RAID was wrong. It will be about 8 cm, and so roughly the same size as the other
2016-12-07Global sea levels would rise by several metres if the Greenland Ice Sheet melted completely. Two studies have examined its past behaviour in an effort to evaluate its vulnerability in a warming world — and have come to seemingly conflicting conclusions. Two geochemists and a glaciologist discuss the issues. See Letters p.252 & p.256
2016-12-07Viruses can be attacked by parasitic viruses, which compete with them for cellular resources. It emerges that one such parasitic virus can defend a host-cell population from a viral attack. See Letter p.288
2016-12-07The chemical composition of a massive galaxy in the early Universe reveals an extremely short period of star formation. This result could challenge our ideas about the evolution of galaxies and of the Universe itself. See Letter p.248
2016-12-07Electrical oscillations generated by neural circuits are disrupted in Alzheimer's disease. Restoring these oscillations in mouse models activates immune cells to clear disease-associated amyloid-β protein from the brain. See Article p.230
2016-12-07In 1976, it was demonstrated that tiny wobbles in Earth's orbit led to the great ice-age cycles of the past few million years. This finding had wide implications for climate science and the details remain hotly debated today.
2016-12-0750 Years AgoAt the neuromuscular junction1, as well as at neuronal synapses2, calcium plays an essential and direct part in the process whereby depolarization of the presynaptic nerve terminal leads to release of the transmitter substance. It is also known
2016-11-30Nuclear DNA from human eggs that harbour mutations in the DNA of organelles called mitochondria has been successfully transferred to donor eggs, bringing the prospect of therapy for mitochondrial diseases a step closer. See Letter p.270
2016-11-30Human stem cells that can give rise to every cell type in the body are major players in biomedical research. A molecular analysis of human embryos might help to make these cultured cells more authentic imitations of their in vivo counterparts.
2016-12-07The concept of randomness plays an important part in many disciplines. On the one hand, the question of whether random processes exist is fundamental for our understanding of nature. On the other, randomness is a resource for cryptography, algorithms and simulations. Standard methods for generating
2016-11-28Wild and managed pollinators provide a wide range of benefits to society in terms of contributions to food security, farmer and beekeeper livelihoods, social and cultural values, as well as the maintenance of wider biodiversity and ecosystem stability. Pollinators face numerous threats, including changes in
2016-12-07Changes in gamma oscillations (20–50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of
2016-10-26R-2-hydroxyglutarate accumulates to millimolar levels in cancer cells with gain-of-function isocitrate dehydrogenase 1/2 mutations. These levels of R-2-hydroxyglutarate affect 2-oxoglutarate-dependent dioxygenases. Both metabolite enantiomers, R- and S-2-hydroxyglutarate, are detectible in healthy individuals, yet their physiological function remains elusive. Here we show
2016-11-30N6-methyladenosine RNA (m6A) is a prevalent messenger RNA modification in vertebrates. Although its functions in the regulation of post-transcriptional gene expression are beginning to be unveiled, the precise roles of m6A during development of complex organisms remain unclear. Here
2016-12-07Unlike spiral galaxies such as the Milky Way, the majority of the stars in massive elliptical galaxies were formed in a short period early in the history of the Universe. The duration of this formation period can be measured using the ratio of magnesium to iron abundance ([Mg/Fe]) in spectra, which reflects the relative enrichment by core-collapse and type Ia supernovae. For local galaxies, [Mg/Fe] probes the combined formation history of all stars currently in the galaxy, including younger and metal-poor stars that were added during late-time mergers. Therefore, to directly constrain the initial star-formation period, we must study galaxies at earlier epochs. The most distant galaxy for which [Mg/Fe] had previously been measured is at a redshift of z ≈ 1.4, with [Mg/Fe] = . A slightly earlier epoch (z ≈ 1.6) was probed by combining the spectra of 24 massive quiescent galaxies, yielding an average [Mg/Fe] = 0.31 ± 0.12 (ref. 7). However, the relatively low signal-to-noise ratio of the data and the use of index analysis techniques for both of these studies resulted in measurement errors that are too large to allow us to form strong conclusions. Deeper spectra at even earlier epochs in combination with analysis techniques based on full spectral fitting are required to precisely measure the abundance pattern shortly after the major star-forming phase (z > 2). Here we report a measurement of [Mg/Fe] for a massive quiescent galaxy at a redshift of z = 2.1, when the Universe was three billion years old. With [Mg/Fe] = 0.59 ± 0.11, this galaxy is the most Mg-enhanced massive galaxy found so far, having twice the Mg enhancement of similar-mass galaxies today. The abundance pattern of the galaxy is consistent with enrichment exclusively by core-collapse supernovae and with a star-formation timescale of 0.1 to 0.5 billion years—characteristics that are similar to population II stars in the Milky Way. With an average past star-formation rate of 600 to 3,000 solar masses per year, this galaxy was among the most vigorous star-forming galaxies in the Universe.
2016-12-07The Greenland Ice Sheet (GIS) contains the equivalent of 7.4 metres of global sea-level rise. Its stability in our warming climate is therefore a pressing concern. However, the sparse proxy evidence of the palaeo-stability of the GIS means that its history is controversial (compare refs 2 and 3 to ref. 4). Here we show that Greenland was deglaciated for extended periods during the Pleistocene epoch (from 2.6 million years ago to 11,700 years ago), based on new measurements of cosmic-ray-produced beryllium and aluminium isotopes (10Be and 26Al) in a bedrock core from beneath an ice core near the GIS summit. Models indicate that when this bedrock site is ice-free, any remaining ice is concentrated in the eastern Greenland highlands and the GIS is reduced to less than ten per cent of its current volume. Our results narrow the spectrum of possible GIS histories: the longest period of stability of the present ice sheet that is consistent with the measurements is 1.1 million years, assuming that this was preceded by more than 280,000 years of ice-free conditions. Other scenarios, in which Greenland was ice-free during any or all Pleistocene interglacials, may be more realistic. Our observations are incompatible with most existing model simulations that present a continuously existing Pleistocene GIS. Future simulations of the GIS should take into account that Greenland was nearly ice-free for extended periods under Pleistocene climate forcing.
2016-12-07Climate models show that ice-sheet melt will dominate sea-level rise over the coming centuries, but our understanding of ice-sheet variations before the last interglacial 125,000 years ago remains fragmentary. This is because terrestrial deposits of ancient glacial and interglacial periods are overrun and eroded by more recent glacial advances, and are therefore usually rare, isolated and poorly dated. In contrast, material shed almost continuously from continents is preserved as marine sediment that can be analysed to infer the time-varying state of major ice sheets. Here we show that the East Greenland Ice Sheet existed over the past 7.5 million years, as indicated by beryllium and aluminium isotopes (10Be and 26Al) in quartz sand removed by deep, ongoing glacial erosion on land and deposited offshore in the marine sedimentary record. During the early Pleistocene epoch, ice cover in East Greenland was dynamic; in contrast, East Greenland was mostly ice-covered during the mid-to-late Pleistocene. The isotope record we present is consistent with distinct signatures of changes in ice sheet behaviour coincident with major climate transitions. Although our data are continuous, they are from low-deposition-rate sites and sourced only from East Greenland. Consequently, the signal of extensive deglaciation during short, intense interglacials could be missed or blurred, and we cannot distinguish between a remnant ice sheet in the East Greenland highlands and a diminished continent-wide ice sheet. A clearer constraint on the behaviour of the ice sheet during past and, ultimately, future interglacial warmth could be produced by 10Be and 26Al records from a coring site with a higher deposition rate. Nonetheless, our analysis challenges the possibility of complete and extended deglaciation over the past several million years.
2016-11-14Seafloor spreading is largely unobserved because 98 per cent of the global mid-ocean-ridge system is below the ocean surface. Our understanding of the dynamic processes that control seafloor spreading is thus inferred largely from geophysical observations of spreading events on land at Afar in East Africa and Iceland. However, these are slow-spreading centres influenced by mantle plumes. The roles of magma pressure and tectonic stress in the development of seafloor spreading are still unclear. Here we use seismic observations to show that the most recent eruption at the fast-spreading East Pacific Rise just North of the Equator initiated at a melt-rich segment about 5 kilometres long. The change in static stress then promoted almost-concurrent rupturing along at least 35 kilometres of the ridge axis, where tectonic stress had built up to a critical level, triggering magma movement. The location of impulsive seismic events indicative of lava reaching the seafloor suggests that lava subsequently erupted from multiple isolated magma lenses (reservoir chambers) with variable magma ascent rates, mostly within 48 hours. Therefore, even at magmatically robust fast-spreading ridges, a substantial portion of the spreading may be due to tectonic stress building up to a critical level rather than magma overpressure in the underlying magma lenses.
2016-11-30Land-use intensification is a major driver of biodiversity loss. Alongside reductions in local species diversity, biotic homogenization at larger spatial scales is of great concern for conservation. Biotic homogenization means a decrease in β-diversity (the compositional dissimilarity between sites). Most studies have investigated losses in local (α)-diversity and neglected biodiversity loss at larger spatial scales. Studies addressing β-diversity have focused on single or a few organism groups (for example, ref. 4), and it is thus unknown whether land-use intensification homogenizes communities at different trophic levels, above- and belowground. Here we show that even moderate increases in local land-use intensity (LUI) cause biotic homogenization across microbial, plant and animal groups, both above- and belowground, and that this is largely independent of changes in α-diversity. We analysed a unique grassland biodiversity dataset, with abundances of more than 4,000 species belonging to 12 trophic groups. LUI, and, in particular, high mowing intensity, had consistent effects on β-diversity across groups, causing a homogenization of soil microbial, fungal pathogen, plant and arthropod communities. These effects were nonlinear and the strongest declines in β-diversity occurred in the transition from extensively managed to intermediate intensity grassland. LUI tended to reduce local α-diversity in aboveground groups, whereas the α-diversity increased in belowground groups. Correlations between the β-diversity of different groups, particularly between plants and their consumers, became weaker at high LUI. This suggests a loss of specialist species and is further evidence for biotic homogenization. The consistently negative effects of LUI on landscape-scale biodiversity underscore the high value of extensively managed grasslands for conserving multitrophic biodiversity and ecosystem service provision. Indeed, biotic homogenization rather than local diversity loss could prove to be the most substantial consequence of land-use intensification.
2016-11-30Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children, with disease severity dependent on the specific gene mutation and the ratio of mutant to wild-type mtDNA (heteroplasmy) in each cell and tissue. Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States. Mitochondrial replacement therapies or techniques (MRT) circumventing mother–to–child mtDNA disease transmission involve replacement of oocyte maternal mtDNA. Here we report MRT outcomes in several families with common mtDNA syndromes. The mother’s oocytes were of normal quality and mutation levels correlated with those in existing children. Efficient replacement of oocyte mutant mtDNA was performed by spindle transfer, resulting in embryos containing >99% donor mtDNA. Donor mtDNA was stably maintained in embryonic stem cells (ES cells) derived from most embryos. However, some ES cell lines demonstrated gradual loss of donor mtDNA and reversal to the maternal haplotype. In evaluating donor–to–maternal mtDNA interactions, it seems that compatibility relates to mtDNA replication efficiency rather than to mismatch or oxidative phosphorylation dysfunction. We identify a polymorphism within the conserved sequence box II region of the D-loop as a plausible cause of preferential replication of specific mtDNA haplotypes. In addition, some haplotypes confer proliferative and growth advantages to cells. Hence, we propose a matching paradigm for selecting compatible donor mtDNA for MRT.
2016-11-28Platelet-derived growth factor receptor α (PDGFRα) exhibits divergent effects in skeletal muscle. At physiological levels, signalling through this receptor promotes muscle development in growing embryos and angiogenesis in regenerating adult muscle. However, both increased PDGF ligand abundance and enhanced PDGFRα pathway activity cause pathological fibrosis. This excessive collagen deposition, which is seen in aged and diseased muscle, interferes with muscle function and limits the effectiveness of gene- and cell-based therapies for muscle disorders. Although compelling evidence exists for the role of PDGFRα in fibrosis, little is known about the cells through which this pathway acts. Here we show in mice that PDGFRα signalling regulates a population of muscle-resident fibro/adipogenic progenitors (FAPs) that play a supportive role in muscle regeneration but may also cause fibrosis when aberrantly regulated. We found that FAPs produce multiple transcriptional variants of Pdgfra with different polyadenylation sites, including an intronic variant that codes for a protein isoform containing a truncated kinase domain. This variant, upregulated during regeneration, acts as a decoy to inhibit PDGF signalling and to prevent FAP over-activation. Moreover, increasing the expression of this isoform limits fibrosis in vivo in mice, suggesting both biological relevance and therapeutic potential of modulating polyadenylation patterns in stem-cell populations.
2016-10-31The Enterobacteriaceae are a family of Gram-negative bacteria that include commensal organisms as well as primary and opportunistic pathogens that are among the leading causes of morbidity and mortality worldwide. Although Enterobacteriaceae often comprise less than 1% of a healthy intestine’s microbiota, some of these organisms can bloom in the inflamed gut; expansion of enterobacteria is a hallmark of microbial imbalance known as dysbiosis. Microcins are small secreted proteins that possess antimicrobial activity in vitro, but whose role in vivo has been unclear. Here we demonstrate that microcins enable the probiotic bacterium Escherichia coli Nissle 1917 (EcN) to limit the expansion of competing Enterobacteriaceae (including pathogens and pathobionts) during intestinal inflammation. Microcin-producing EcN limits the growth of competitors in the inflamed intestine, including commensal E. coli, adherent–invasive E. coli and the related pathogen Salmonella enterica. Moreover, only therapeutic administration of the wild-type, microcin-producing EcN to mice previously infected with S. enterica substantially reduced intestinal colonization by the pathogen. Our work provides the first evidence that microcins mediate inter- and intraspecies competition among the Enterobacteriaceae in the inflamed gut. Moreover, we show that microcins can act as narrow-spectrum therapeutics to inhibit enteric pathogens and reduce enterobacterial blooms.
2016-11-09The development of immunologic interventions that can target the viral reservoir in HIV-1-infected individuals is a major goal of HIV-1 research. However, little evidence exists that the viral reservoir can be sufficiently targeted to improve virologic control following discontinuation of antiretroviral therapy. Here we show that therapeutic vaccination with Ad26/MVA (recombinant adenovirus serotype 26 (Ad26) prime, modified vaccinia Ankara (MVA) boost) and stimulation of TLR7 (Toll-like receptor 7) improves virologic control and delays viral rebound following discontinuation of antiretroviral therapy in SIV-infected rhesus monkeys that began antiretroviral therapy during acute infection. Therapeutic vaccination with Ad26/MVA resulted in a marked increase in the magnitude and breadth of SIV-specific cellular immune responses in virologically suppressed, SIV-infected monkeys. TLR7 agonist administration led to innate immune stimulation and cellular immune activation. The combination of Ad26/MVA vaccination and TLR7 stimulation resulted in decreased levels of viral DNA in lymph nodes and peripheral blood, and improved virologic control and delayed viral rebound following discontinuation of antiretroviral therapy. The breadth of cellular immune responses correlated inversely with set point viral loads and correlated directly with time to viral rebound. These data demonstrate the potential of therapeutic vaccination combined with innate immune stimulation as a strategy aimed at a functional cure for HIV-1 infection.
2016-12-07Endogenous viral elements are increasingly found in eukaryotic genomes, yet little is known about their origins, dynamics, or function. Here we provide a compelling example of a DNA virus that readily integrates into a eukaryotic genome where it acts as an inducible antiviral defence system. We found that the virophage mavirus, a parasite of the giant Cafeteria roenbergensis virus (CroV), integrates at multiple sites within the nuclear genome of the marine protozoan Cafeteria roenbergensis. The endogenous mavirus is structurally and genetically similar to eukaryotic DNA transposons and endogenous viruses of the Maverick/Polinton family. Provirophage genes are not constitutively expressed, but are specifically activated by superinfection with CroV, which induces the production of infectious mavirus particles. Virophages can inhibit the replication of mimivirus-like giant viruses and an anti-viral protective effect of provirophages on their hosts has been hypothesized. We find that provirophage-carrying cells are not directly protected from CroV; however, lysis of these cells releases infectious mavirus particles that are then able to suppress CroV replication and enhance host survival during subsequent rounds of infection. The microbial host–parasite interaction described here involves an altruistic aspect and suggests that giant-virus-induced activation of provirophages might be ecologically relevant in natural protist populations.
2016-11-30Complex biological processes are often performed by self-organizing nanostructures comprising multiple classes of macromolecules, such as ribosomes (proteins and RNA) or enveloped viruses (proteins, nucleic acids and lipids). Approaches have been developed for designing self-assembling structures consisting of either nucleic acids or proteins, but strategies for engineering hybrid biological materials are only beginning to emerge. Here we describe the design of self-assembling protein nanocages that direct their own release from human cells inside small vesicles in a manner that resembles some viruses. We refer to these hybrid biomaterials as ‘enveloped protein nanocages’ (EPNs). Robust EPN biogenesis requires protein sequence elements that encode three distinct functions: membrane binding, self-assembly, and recruitment of the endosomal sorting complexes required for transport (ESCRT) machinery. A variety of synthetic proteins with these functional elements induce EPN biogenesis, highlighting the modularity and generality of the design strategy. Biochemical analyses and cryo-electron microscopy reveal that one design, EPN-01, comprises small (~100 nm) vesicles containing multiple protein nanocages that closely match the structure of the designed 60-subunit self-assembling scaffold. EPNs that incorporate the vesicular stomatitis viral glycoprotein can fuse with target cells and deliver their contents, thereby transferring cargoes from one cell to another. These results show how proteins can be programmed to direct the formation of hybrid biological materials that perform complex tasks, and establish EPNs as a class of designed, modular, genetically-encoded nanomaterials that can transfer molecules between cells.
2016-11-30Chromosomes are folded into highly compacted structures to accommodate physical constraints within nuclei and to regulate access to genomic information. Recently, global mapping of pairwise contacts showed that loops anchoring topological domains (TADs) are highly conserved between cell types and species. Whether pairwise loops synergize to form higher-order structures is still unclear. Here we develop a conformation capture assay to study higher-order organization using chromosomal walks (C-walks) that link multiple genomic loci together into proximity chains in human and mouse cells. This approach captures chromosomal structure at varying scales. Inter-chromosomal contacts constitute only 7–10% of the pairs and are restricted by interfacing TADs. About half of the C-walks stay within one chromosome, and almost half of those are restricted to intra-TAD spaces. C-walks that couple 2–4 TADs indicate stochastic associations between transcriptionally active, early replicating loci. Targeted analysis of thousands of 3-walks anchored at highly expressed genes support pairwise, rather than hub-like, chromosomal topology at active loci. Polycomb-repressed Hox domains are shown by the same approach to enrich for synergistic hubs. Together, the data indicate that chromosomal territories, TADs, and intra-TAD loops are primarily driven by nested, possibly dynamic, pairwise contacts.
2016-11-30N6-methyladenosine (m6A) is the most common internal modification of eukaryotic messenger RNA (mRNA) and is decoded by YTH domain proteins. The mammalian mRNA m6A methylosome is a complex of nuclear proteins that includes METTL3 (methyltransferase-like 3), METTL14, WTAP (Wilms tumour 1-associated protein) and KIAA1429. Drosophila has corresponding homologues named Ime4 and KAR4 (Inducer of meiosis 4 and Karyogamy protein 4), and Female-lethal (2)d (Fl(2)d) and Virilizer (Vir). In Drosophila, fl(2)d and vir are required for sex-dependent regulation of alternative splicing of the sex determination factor Sex lethal (Sxl). However, the functions of m6A in introns in the regulation of alternative splicing remain uncertain. Here we show that m6A is absent in the mRNA of Drosophila lacking Ime4. In contrast to mouse and plant knockout models, Drosophila Ime4-null mutants remain viable, though flightless, and show a sex bias towards maleness. This is because m6A is required for female-specific alternative splicing of Sxl, which determines female physiognomy, but also translationally represses male-specific lethal 2 (msl-2) to prevent dosage compensation in females. We further show that the m6A reader protein YT521-B decodes m6A in the sex-specifically spliced intron of Sxl, as its absence phenocopies Ime4 mutants. Loss of m6A also affects alternative splicing of additional genes, predominantly in the 5′ untranslated region, and has global effects on the expression of metabolic genes. The requirement of m6A and its reader YT521-B for female-specific Sxl alternative splicing reveals that this hitherto enigmatic mRNA modification constitutes an ancient and specific mechanism to adjust levels of gene expression.