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Nature



Nature is a weekly international journal publishing the finest peer-reviewed research in all fields of science and technology on the basis of its originality, importance, interdisciplinary interest, timeliness, accessibility, elegance and surprising concl



 



A more personal view of human-gene regulation
A long-planned effort to examine gene expression and gene regulation in all the major tissues in the human body across many people comes to fruition.



Climate meetings pose serious test in the Trump era

2017-10-10

Annual jamborees fail to ignite public passion but are crucial to progress on global-warming.



Marine snow falls heaviest at the Equator

2017-10-11

Organic matter drifts down to the equatorial ocean floor in distinct patterns.



Developing nations need more than just money

2017-10-10

Grants from big science funders can be hard to use without better administration and mutual understanding, says Rana Dajani.



ResearchGate lawsuit, walrus spat and a Second World War shipwreck

2017-10-11

The week in science: 6–12 October 2017.



Navajo Nation reconsiders ban on genetic research

2017-10-06

Tribal leaders are developing a policy for genetic research and data sharing, potentially ending a 15-year moratorium.



Scientists plead with Brazilian government to restore funding

2017-10-04

If officials don't act soon, research institutions could start shutting down next year.



Cryo-electron microscopy wins chemistry Nobel

2017-10-04

Jacques Dubochet, Joachim Frank and Richard Henderson share the prize for developing a technique to image biomolecules.



The ambitious effort to document California’s changing deserts

2017-10-11

Ecologists catalogue bird and mammal populations as warming transforms Death Valley.



Gene-expression study raises thorny ethical issues
Project obtains tissues from recently deceased individuals to look for the origins of disease.



How the United States plans to trap its biggest stash of nuclear-weapons waste in glass

2017-10-10

After decades of delays, a challenging clean-up project is gaining ground.



The rise and fall and rise again of 23andMe

2017-10-11

How Anne Wojcicki led her company from the brink of failure to scientific pre-eminence.



The future of DNA sequencing
Eric D. Green, Edward M. Rubin and Maynard V. Olson speculate on the next forty years of the applications, from policing to data storage.



Build on the outer space treaty

2017-10-09

Fifty years on, the agreement is being pushed to its limits by changing geopolitics, technology and commercial interests, warns Joan Johnson-Freese.



Physics: A classical toolkit

2017-10-11

Malcolm Longair extols a long-heralded tome by Roger Blandford and 2017 Nobel laureate Kip Thorne.



Chemistry: Explosive moments in the laboratory

2017-10-11

Mark Peplow surveys a gorgeous gala of reactions in Theodore Gray's new book.



Books in brief

2017-10-11

Barbara Kiser reviews five of the week's best science picks.



Cancer care: Tap latent source of frugal cancer ideas

2017-10-11

Richard Sullivan and colleagues propose ways to improve cancer care globally (Nature549, 325–328; 2017). For lower-income countries, we suggest that local measures could contribute if they were promoted and developed globally with the help of high-income countries.'Frugal



Natural hazards: Risk assessments face legal scrutiny

2017-10-11

Scientific risk assessments of natural hazards are increasingly subjected to legal scrutiny, given the costly damage of such events (see, for example, Nature548, 508–509; 2017). The reputations of the scientists, civil-protection managers and politicians tasked with reducing societal risk



Countries: Avoid glib terms of development status

2017-10-11

I suggest that the description of countries as 'developing' or 'developed' should be used with caution — or not at all — in the scientific literature. These categorizations are largely subjective, as shown by their controversial and inconsistent usage among global organizations, which have to



Brain modelling: Does the brain control foraging?

2017-10-11

The quest of the International Brain Lab (IBL) to determine the role of the brain in foraging behaviour (Nature549, 319–320; 2017) follows centuries of testing the outcome of different brain manipulations. Those experiments failed to link correlations with



Predatory journals: Research that isn't read doesn't exist

2017-10-11

David Moher and colleagues underline how harmful predatory journals are in medicine and related fields (Nature549, 23–25; 2017). In other research areas that are less well funded, such as my own field of palaeontology, my hunch is that



Career change: It's never too late to switch

2017-10-11

With willpower and suitable financial means, you can start a science career at any age.



Writing takes work

2017-10-11

Professors and students alike can benefit from attending a writers' workshop, says Eli Lazarus.






Climate change

2017-10-11




Sea change

2017-10-11

The increasing acidity of our seas is a threat to marine life that for many species may be impossible to overcome.



Policy: Getting political

2017-10-11

Is running for office the next step for researchers in the fight against climate inaction?



The real climate debate

2017-10-11

In the scientific community, the big question is not whether action on climate change is required, but what form it should take — and the part that scientists should play. Three Nobel laureates and three early-career researchers gave their thoughts to Nature on the current state of climate action worldwide and the place of science in society.



Emissions: We have the technology

2017-10-11

Carbon capture and storage will be crucial for mitigating climate change and rebuilding the world's energy infrastructure.



Correction

2017-10-11

The Books & Arts article 'Final ascent of physics' (Nature549, 331–332; 2017) incorrectly stated that Special Relativity and Classical Field Theory is the last book in the Theoretical Minimum series, and described it as “historical” instead of



Human genomics: Cracking the regulatory code

2017-10-11

A collection of papers catalogues the associations between genetic variation and gene expression in healthy tissues – the largest analysis of this kind so far. See Article p.204 & Letters p.239, p.244 & p.249



Mathematics: A pariah finds a home

2017-10-04

Pariahs are fundamental building blocks in a branch of mathematics called group theory, but seem to be unconnected from both physics and other areas of mathematics. Such a connection has now been identified.



Cancer: Tumours addicted to drugs are vulnerable

2017-10-04

Cancer cells can develop an 'addiction' to the drugs they are treated with, so that they need the drugs to survive. Analysis of the underlying mechanism reveals a potential clinical strategy for harnessing this phenomenon. See Letter p.270



50 & 100 Years Ago

2017-10-11

50 Years AgoLearned behaviour is reported to be transmitted by injecting into untrained animals fractions or homogenates, containing RNA, from the cerebral hemispheres of trained rats ... The transfer problem is very important for the understanding of memory and learning, and we have carried



Engineering: Liquid metal pumped at a record temperature

2017-10-11

Although liquid metals are effective fluids for heat transfer, pumping them at high temperatures is limited by their corrosiveness to solid metals. A clever pump design addresses this challenge using only ceramics. See Article p.199



Obesity: Receptors identified for a weight regulator

2017-09-27

The discovery of the receptors for the protein GDF15 suggests that it regulates food uptake through the emergency pathway — a neuronal circuit that causes weight loss in response to cancer, tissue damage and stress. See Letter p.255



Astronomy: Ring detected around a dwarf planet

2017-10-11

Observations of the distant dwarf planet Haumea constrain its size, shape and density, and reveal an encircling planetary ring. The discovery suggests that rings are not as rare in the Solar System as previously thought. See Letter p.219



Correction

2017-10-11

The News & Views 'Neuroscience: Mum's bacteria linked to baby's behaviour' by CraigM.Powell (Nature549, 466–467; 10.1038/nature241392017) omitted to mention that the author had declared competing financial interests. The News & Views has been



Pumping liquid metal at high temperatures up to 1,673 kelvin

2017-10-11

Heat is fundamental to power generation and many industrial processes, and is most useful at high temperatures because it can be converted more efficiently to other types of energy. However, efficient transportation, storage and conversion of heat at extreme temperatures (more than about 1,300 kelvin)



Genetic effects on gene expression across human tissues

2017-10-11

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse



The transcription fidelity factor GreA impedes DNA break repair

2017-10-04

Homologous recombination repairs DNA double-strand breaks and must function even on actively transcribed DNA. Because break repair prevents chromosome loss, the completion of repair is expected to outweigh the transcription of broken templates. However, the interplay between DNA break repair and transcription processivity is unclear.



The size, shape, density and ring of the dwarf planet Haumea from a stellar occultation

2017-10-11

Haumea—one of the four known trans-Neptunian dwarf planets—is a very elongated and rapidly rotating body. In contrast to other dwarf planets, its size, shape, albedo and density are not well constrained. The Centaur Chariklo was the first body other than a giant planet known to have a ring system, and the Centaur Chiron was later found to possess something similar to Chariklo’s rings. Here we report observations from multiple Earth-based observatories of Haumea passing in front of a distant star (a multi-chord stellar occultation). Secondary events observed around the main body of Haumea are consistent with the presence of a ring with an opacity of 0.5, width of 70 kilometres and radius of about 2,287 kilometres. The ring is coplanar with both Haumea’s equator and the orbit of its satellite Hi’iaka. The radius of the ring places it close to the 3:1 mean-motion resonance with Haumea’s spin period—that is, Haumea rotates three times on its axis in the time that a ring particle completes one revolution. The occultation by the main body provides an instantaneous elliptical projected shape with axes of about 1,704 kilometres and 1,138 kilometres. Combined with rotational light curves, the occultation constrains the three-dimensional orientation of Haumea and its triaxial shape, which is inconsistent with a homogeneous body in hydrostatic equilibrium. Haumea’s largest axis is at least 2,322 kilometres, larger than previously thought, implying an upper limit for its density of 1,885 kilograms per cubic metre and a geometric albedo of 0.51, both smaller than previous estimates. In addition, this estimate of the density of Haumea is closer to that of Pluto than are previous estimates, in line with expectations. No global nitrogen- or methane-dominated atmosphere was detected.



Light-field-driven currents in graphene

2017-09-25

The ability to steer electrons using the strong electromagnetic field of light has opened up the possibility of controlling electron dynamics on the sub-femtosecond (less than 10−15 seconds) timescale. In dielectrics and semiconductors, various light-field-driven effects have been explored, including high-harmonic generation, sub-optical-cycle interband population transfer and the non-perturbative change of the transient polarizability. In contrast, much less is known about light-field-driven electron dynamics in narrow-bandgap systems or in conductors, in which screening due to free carriers or light absorption hinders the application of strong optical fields. Graphene is a promising platform with which to achieve light-field-driven control of electrons in a conducting material, because of its broadband and ultrafast optical response, weak screening and high damage threshold. Here we show that a current induced in monolayer graphene by two-cycle laser pulses is sensitive to the electric-field waveform, that is, to the exact shape of the optical carrier field of the pulse, which is controlled by the carrier-envelope phase, with a precision on the attosecond (10−18 seconds) timescale. Such a current, dependent on the carrier-envelope phase, shows a striking reversal of the direction of the current as a function of the driving field amplitude at about two volts per nanometre. This reversal indicates a transition of light–matter interaction from the weak-field (photon-driven) regime to the strong-field (light-field-driven) regime, where the intraband dynamics influence interband transitions. We show that in this strong-field regime the electron dynamics are governed by sub-optical-cycle Landau–Zener–Stückelberg interference, composed of coherent repeated Landau–Zener transitions on the femtosecond timescale. Furthermore, the influence of this sub-optical-cycle interference can be controlled with the laser polarization state. These coherent electron dynamics in graphene take place on a hitherto unexplored timescale, faster than electron–electron scattering (tens of femtoseconds) and electron–phonon scattering (hundreds of femtoseconds). We expect these results to have direct ramifications for band-structure tomography and light-field-driven petahertz electronics.



Layer-by-layer assembly of two-dimensional materials into wafer-scale heterostructures

2017-09-20

High-performance semiconductor films with vertical compositions that are designed to atomic-scale precision provide the foundation for modern integrated circuitry and novel materials discovery. One approach to realizing such films is sequential layer-by-layer assembly, whereby atomically thin two-dimensional building blocks are vertically stacked, and held together by van der Waals interactions. With this approach, graphene and transition-metal dichalcogenides—which represent one- and three-atom-thick two-dimensional building blocks, respectively—have been used to realize previously inaccessible heterostructures with interesting physical properties. However, no large-scale assembly method exists at present that maintains the intrinsic properties of these two-dimensional building blocks while producing pristine interlayer interfaces, thus limiting the layer-by-layer assembly method to small-scale proof-of-concept demonstrations. Here we report the generation of wafer-scale semiconductor films with a very high level of spatial uniformity and pristine interfaces. The vertical composition and properties of these films are designed at the atomic scale using layer-by-layer assembly of two-dimensional building blocks under vacuum. We fabricate several large-scale, high-quality heterostructure films and devices, including superlattice films with vertical compositions designed layer-by-layer, batch-fabricated tunnel device arrays with resistances that can be tuned over four orders of magnitude, band-engineered heterostructure tunnel diodes, and millimetre-scale ultrathin membranes and windows. The stacked films are detachable, suspendable and compatible with water or plastic surfaces, which will enable their integration with advanced optical and mechanical systems.



Patchy particles made by colloidal fusion

2017-09-18

Patches on the surfaces of colloidal particles provide directional information that enables the self-assembly of the particles into higher-order structures. Although computational tools can make quantitative predictions and can generate design rules that link the patch motif of a particle to its internal microstructure and to the emergent properties of the self-assembled materials, the experimental realization of model systems of particles with surface patches (or ‘patchy’ particles) remains a challenge. Synthetic patchy colloidal particles are often poor geometric approximations of the digital building blocks used in simulations and can only rarely be manufactured in sufficiently high yields to be routinely used as experimental model systems. Here we introduce a method, which we refer to as colloidal fusion, for fabricating functional patchy particles in a tunable and scalable manner. Using coordination dynamics and wetting forces, we engineer hybrid liquid–solid clusters that evolve into particles with a range of patchy surface morphologies on addition of a plasticizer. We are able to predict and control the evolutionary pathway by considering surface-energy minimization, leading to two main branches of product: first, spherical particles with liquid surface patches, capable of forming curable bonds with neighbouring particles to assemble robust supracolloidal structures; and second, particles with a faceted liquid compartment, which can be cured and purified to yield colloidal polyhedra. These findings outline a scalable strategy for the synthesis of patchy particles, first by designing their surface patterns by computer simulation, and then by recreating them in the laboratory with high fidelity.



The impact of rare variation on gene expression across tissues

2017-10-11

Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.



Landscape of X chromosome inactivation across human tissues

2017-10-11

X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of ‘escape’ from inactivation varying between genes and individuals. The extent to which XCI is shared between cells and tissues remains poorly characterized, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression and phenotypic traits. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.



Dynamic landscape and regulation of RNA editing in mammals

2017-10-11

Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules. Although many editing sites have recently been discovered, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.



Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15

2017-09-27

Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure. In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand. Recent studies have identified brain areas outside the hypothalamus that are activated under these ‘non-homeostatic’ conditions, but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the ‘emergency circuit’ that shapes feeding responses to stressful conditions. GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases. By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.



Hippo pathway deficiency reverses systolic heart failure after infarction

2017-10-04

Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls. Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.



TORC1 organized in inhibited domains (TOROIDs) regulate TORC1 activity

2017-10-04

The target of rapamycin (TOR) is a eukaryotic serine/threonine protein kinase that functions in two distinct complexes, TORC1 and TORC2, to regulate growth and metabolism. GTPases, responding to signals generated by abiotic stressors, nutrients, and, in metazoans, growth factors, play an important but poorly understood role in TORC1 regulation. Here we report that, in budding yeast, glucose withdrawal (which leads to an acute loss of TORC1 kinase activity) triggers a similarly rapid Rag GTPase-dependent redistribution of TORC1 from being semi-uniform around the vacuolar membrane to a single, vacuole-associated cylindrical structure visible by super-resolution optical microscopy. Three-dimensional reconstructions of cryo-electron micrograph images of these purified cylinders demonstrate that TORC1 oligomerizes into a higher-level hollow helical assembly, which we name a TOROID (TORC1 organized in inhibited domain). Fitting of the recently described mammalian TORC1 structure into our helical map reveals that oligomerization leads to steric occlusion of the active site. Guided by the implications from our reconstruction, we present a TOR1 allele that prevents both TOROID formation and TORC1 inactivation in response to glucose withdrawal, demonstrating that oligomerization is necessary for TORC1 inactivation. Our results reveal a novel mechanism by which Rag GTPases regulate TORC1 activity and suggest that the reversible assembly and/or disassembly of higher-level structures may be an underappreciated mechanism for the regulation of protein kinases.



Cancer drug addiction is relayed by an ERK2-dependent phenotype switch

2017-10-04

Observations from cultured cells, animal models and patients raise the possibility that the dependency of tumours on the therapeutic drugs to which they have acquired resistance represents a vulnerability with potential applications in cancer treatment. However, for this drug addiction trait to become of clinical interest, we must first define the mechanism that underlies it. We performed an unbiased CRISPR–Cas9 knockout screen on melanoma cells that were both resistant and addicted to inhibition of the serine/threonine-protein kinase BRAF, in order to functionally mine their genome for ‘addiction genes’. Here we describe a signalling pathway comprising ERK2 kinase and JUNB and FRA1 transcription factors, disruption of which allowed addicted tumour cells to survive on treatment discontinuation. This occurred in both cultured cells and mice and was irrespective of the acquired drug resistance mechanism. In melanoma and lung cancer cells, death induced by drug withdrawal was preceded by a specific ERK2-dependent phenotype switch, alongside transcriptional reprogramming reminiscent of the epithelial–mesenchymal transition. In melanoma cells, this reprogramming caused the shutdown of microphthalmia-associated transcription factor (MITF), a lineage survival oncoprotein; restoring this protein reversed phenotype switching and prevented the lethality associated with drug addiction. In patients with melanoma that had progressed during treatment with a BRAF inhibitor, treatment cessation was followed by increased expression of the receptor tyrosine kinase AXL, which is associated with the phenotype switch. Drug discontinuation synergized with the melanoma chemotherapeutic agent dacarbazine by further suppressing MITF and its prosurvival target, B-cell lymphoma 2 (BCL-2), and by inducing DNA damage in cancer cells. Our results uncover a pathway that underpins drug addiction in cancer cells, which may help to guide the use of alternating therapeutic strategies for enhanced clinical responses in drug-resistant cancers.



A viral Sm-class RNA base-pairs with mRNAs and recruits microRNAs to inhibit apoptosis

2017-10-04

Viruses express several classes of non-coding RNAs; the functions and mechanisms by which most of these act are unknown. Herpesvirus saimiri, a γ-herpesvirus that establishes latency in the T cells of New World primates and has the ability to cause aggressive leukaemias and lymphomas in non-natural hosts, expresses seven small nuclear uracil-rich non-coding RNAs (called HSURs) in latently infected cells. These HSURs associate with Sm proteins, and share biogenesis and structural features with cellular Sm-class small nuclear RNAs. One of these HSURs (HSUR2) base-pairs with two host cellular microRNAs (miR-142-3p and miR-16) but does not affect their abundance or activity, which suggests that its interactions with them perform alternative functions. Here we show that HSUR2 also base-pairs with mRNAs in infected cells. We combined in vivo psoralen-mediated RNA–RNA crosslinking and high-throughput sequencing to identify the mRNAs targeted by HSUR2, which include mRNAs that encode retinoblastoma and factors involved in p53 signalling and apoptosis. We show that HSUR2 represses the expression of target mRNAs and that base-pairing between HSUR2 and miR-142-3p and miR-16 is essential for this repression, suggesting that HSUR2 recruits these two cellular microRNAs to its target mRNAs. Furthermore, we show that HSUR2 uses this mechanism to inhibit apoptosis. Our results uncover a role for this viral Sm-class RNA as a microRNA adaptor in the regulation of gene expression that follows precursor mRNA processing.



RNA targeting with CRISPR–Cas13

2017-10-04

RNA has important and diverse roles in biology, but molecular tools to manipulate and measure it are limited. For example, RNA interference can efficiently knockdown RNAs, but it is prone to off-target effects, and visualizing RNAs typically relies on the introduction of exogenous tags. Here we demonstrate that the class 2 type VI RNA-guided RNA-targeting CRISPR–Cas effector Cas13a (previously known as C2c2) can be engineered for mammalian cell RNA knockdown and binding. After initial screening of 15 orthologues, we identified Cas13a from Leptotrichia wadei (LwaCas13a) as the most effective in an interference assay in Escherichia coli. LwaCas13a can be heterologously expressed in mammalian and plant cells for targeted knockdown of either reporter or endogenous transcripts with comparable levels of knockdown as RNA interference and improved specificity. Catalytically inactive LwaCas13a maintains targeted RNA binding activity, which we leveraged for programmable tracking of transcripts in live cells. Our results establish CRISPR–Cas13a as a flexible platform for studying RNA in mammalian cells and therapeutic development.