Insights into the phylogeny and coding potential of microbial dark matter
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Christian, Rinke↗
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Comparative analysis of the transcriptome across distant species
The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features[1,2,3,4,5,6]. Specifically, we discovered co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we used expression patterns to align the stages in worm and fly development, finding a novel pairing between worm embryo and fly pupae, in addition to the expected embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we found that the extent of non-canonical, non-coding transcription is similar in each organism, per base-pair. Finally, we found in all three organisms the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a “universal model,” based on a single set of organism-independent parameters. Our comparison used the ENCODE-modENCODE RNA resource (Fig. ED1). This resource comprises: (1) deeply sequenced RNA-Seq data from many distinct samples from all three organisms; (2) comprehensive annotation of transcribed elements and (3) uniformly processed, standardized analysis files, focusing on non-coding transcription and expression patterns. Where practical, these datasets match comparable samples across organisms and to other types of functional genomics data. In total, the resource contains 575 different experiments containing >67B sequence reads. It encompasses many different RNA types, including poly(A)+, poly(A)- and ribosomal-RNA-depleted RNA and short and long RNA.
59 BASIC BIOLOGICAL SCIENCES↗
Structural integration in hypoxia-inducible factors
The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-alpha and ARNT (also called HIF-1 beta) subunits. Here we describe crystal structures for each of mouse HIF-2 alpha-ARNT and HIF-1 alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2 alpha-ARNT and HIF-1 alpha-ARNT, wherein ARNT spirals around the outside of each HIF-alpha subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.
Wu, Dalei↗
H4K20me0 marks post-replicative chromatin and recruits the TONSL₋MMS22L DNA repair complex
Here, we report that after DNA replication, chromosomal processes including DNA repair and transcription take place in the context of sister chromatids. While cell cycle regulation can guide these processes globally, mechanisms to distinguish pre- and post-replicative states locally remain unknown. In this paper we reveal that new histones incorporated during DNA replication provide a signature of post-replicative chromatin, read by the human TONSL–MMS22L 1, 2, 3, 4 homologous recombination complex. We identify the TONSL ankyrin repeat domain (ARD) as a reader of histone H4 tails unmethylated at K20 (H4K20me0), which are specific to new histones incorporated during DNA replication and mark post-replicative chromatin until the G2/M phase of the cell cycle. Accordingly, TONSL–MMS22L binds new histones H3–H4 both before and after incorporation into nucleosomes, remaining on replicated chromatin until late G2/M. H4K20me0 recognition is required for TONSL–MMS22L binding to chromatin and accumulation at challenged replication forks and DNA lesions. Consequently, TONSL ARD mutants are toxic, compromising genome stability, cell viability and resistance to replication stress. Finally, together, these data reveal a histone-reader-based mechanism for recognizing the post-replicative state, offering a new angle to understand DNA repair with the potential for targeted cancer therapy.
Histone post-translational modifications↗
A communal catalogue reveals Earth’s multiscale microbial diversity
Our growing awareness of the importance and diversity of the microbial world contrasts starkly with our limited understanding of its fundamental structure. Despite remarkable advances in DNA sequence generation, a lack of standardized protocols and common analytical framework impede useful comparison between studies, hindering development of global inferences about microbial life on Earth. Here, we show that with coordinated protocols, exact microbial 16S rRNA gene sequences can be followed across scores of individual studies, revealing patterns of diversity, community structure, and life history strategy at a planetary scale. Using 27,751 crowdsourced environmental samples comprising more than 2.2 billion reads, we find sharp divides between host-associated and free-living communities. We show that the distribution of taxonomic and sequence diversity follows consistent trends across samples types and along gradients of environmental parameters, highlighting some of the global evolutionary patterns and ecological principles that underpin Earth’s microbiome. Here, this dataset provides the most complete environmental survey of our microbial world to date, and serves as a growing reference to provide immediate global context to future microbial surveys.
54 ENVIRONMENTAL SCIENCES↗
Recon3D enables a three-dimensional view of gene variation in human metabolism
Genome-scale network reconstructions have helped uncover the molecular basis of metabolism. Here we present Recon3D, a computational resource that includes three-dimensional (3D) metabolite and protein structure data and enables integrated analyses of metabolic functions in humans. We use Recon3D to functionally characterize mutations associated with disease, and identify metabolic response signatures that are caused by exposure to certain drugs. Recon3D represents the most comprehensive human metabolic network model to date, accounting for 3,288 open reading frames (representing 17% of functionally annotated human genes), 13,543 metabolic reactions involving 4,140 unique metabolites, and 12,890 protein structures. As a result, these data provide a unique resource for investigating molecular mechanisms of human metabolism.
59 BASIC BIOLOGICAL SCIENCES↗
Nascent peptide assists the ribosome in recognizing chemically distinct small molecules
Regulation of gene expression in response to the changing environment is critical for cell survival. For instance, binding of macrolide antibiotics to the ribosome promotes translation arrest at the leader open reading frames ermCL and ermBL, which is necessary for inducing the antibiotic resistance genes ermC and ermB. Cladinose-containing macrolides such as erythromycin (ERY), but not ketolides such as telithromycin (TEL), arrest translation of ermCL, whereas either ERY or TEL stall ermBL translation. How the ribosome distinguishes between chemically similar small molecules is unknown. We show that single amino acid changes in the leader peptide switch the specificity of recognition of distinct molecules, triggering gene activation in response to ERY alone, to TEL alone or to both antibiotics or preventing stalling altogether. Thus, the ribosomal response to chemical signals can be modulated by minute changes in the nascent peptide, suggesting that protein sequences could have been optimized for rendering translation sensitive to environmental cues.
Biochemistry & Molecular Biology↗
Multiple-stable anisotropic magnetoresistance memory in antiferromagnetic MnTe
Commercial magnetic memories rely on the bistability of ordered spins in ferromagnetic materials. Recently, experimental bistable memories have been realized using fully compensated antiferromagnetic metals. Here we demonstrate a multiple-stable memory device in epitaxial MnTe, an antiferromagnetic counterpart of common II–VI semiconductors. Favourable micromagnetic characteristics of MnTe allow us to demonstrate a smoothly varying zero-field antiferromagnetic anisotropic magnetoresistance (AMR) with a harmonic angular dependence on the writing magnetic field angle, analogous to ferromagnets. The continuously varying AMR provides means for the electrical read-out of multiple-stable antiferromagnetic memory states, which we set by heat-assisted magneto-recording and by changing the writing field direction. The multiple stability in our memory is ascribed to different distributions of domains with the Ne´el vector aligned along one of the three magnetic easy axes. The robustness against strong magnetic field perturbations combined with the multiple stability of the magnetic memory states are unique properties of antiferromagnets.
71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
Microwave a.c. conductivity of domain walls in ferroelectric thin films
Ferroelectric domain walls are of great interest as elementary building blocks for future electronic devices due to their intrinsic few-nanometre width, multifunctional properties and field-controlled topology. To realize the electronic functions, domain walls are required to be electrically conducting and addressable non-destructively. However, these properties have been elusive because conducting walls have to be electrically charged, which makes them unstable and uncommon in ferroelectric materials. Here we reveal that spontaneous and recorded domain walls in thin films of lead zirconate and bismuth ferrite exhibit large conductance at microwave frequencies despite being insulating at d.c. We explain this effect by morphological roughening of the walls and local charges induced by disorder with the overall charge neutrality. a.c. conduction is immune to large contact resistance enabling completely non-destructive walls read-out. Finally, this demonstrates a technological potential for harnessing a.c. conduction for oxide electronics and other materials with poor d.c. conduction, particularly at the nanoscale.
36 MATERIALS SCIENCE↗
Direct and simultaneous observation of ultrafast electron and hole dynamics in germanium
Understanding excited carrier dynamics in semiconductors is crucial for the development of photovoltaics and efficient photonic devices. However, overlapping spectral features in optical pump-probe spectroscopy often render assignments of separate electron and hole carrier dynamics ambiguous. Here, ultrafast electron and hole dynamics in germanium nanocrystalline thin films are directly and simultaneously observed by ultrafast transient absorption spectroscopy in the extreme ultraviolet at the germanium M 4,5 edge. We decompose the spectra into contributions of electronic state blocking and photo-induced band shifts at a carrier density of 8 × 10 20 cm –3 . Separate electron and hole relaxation times are observed as a function of hot carrier energies. A first-order electron and hole decay of ~1 ps suggests a Shockley–Read–Hall recombination mechanism. Furthermore, the simultaneous observation of electrons and holes with extreme ultraviolet transient absorption spectroscopy paves the way for investigating few- to sub-femtosecond dynamics of both holes and electrons in complex semiconductor materials and across junctions.
36 MATERIALS SCIENCE↗
Electrical probing of field-driven cascading quantized transitions of skyrmion cluster states in MnSi nanowires
Magnetic skyrmions are topologically stable whirlpool-like spin textures that offer great promise as information carriers for future spintronic devices. To enable such applications, particular attention has been focused on the properties of skyrmions in highly confined geometries such as one-dimensional nanowires. Hitherto, it is still experimentally unclear what happens when the width of the nanowire is comparable to that of a single skyrmion. Here, we achieve this by measuring the magnetoresistance in ultra-narrow MnSi nanowires. We observe quantized jumps in magnetoresistance versus magnetic field curves. By tracking the size dependence of the jump number, we infer that skyrmions are assembled into cluster states with a tunable number of skyrmions, in agreement with the Monte Carlo simulations. Our results enable an electric reading of the number of skyrmions in the cluster states, thus laying a solid foundation to realize skyrmion-based memory devices.
36 MATERIALS SCIENCE↗
Widespread adenine N6-methylation of active genes in fungi
N6-methyldeoxyadenine (6mA) is a noncanonical DNA base modification present at low levels in plant and animal genomes, but its prevalence and association with genome function in other eukaryotic lineages remains poorly understood. We report that abundant 6mA is associated with transcriptionally active genes in early-diverging fungal lineages. Using single-molecule long-read sequencing of 16 diverse fungal genomes, we observed that up to 2.8% of all adenines were methylated in early-diverging fungi, far exceeding levels observed in other eukaryotes and more derived fungi. 6mA occurred symmetrically at ApT dinucleotides and was concentrated in dense methylated adenine clusters surrounding the transcriptional start sites of expressed genes; its distribution was inversely correlated with that of 5-methylcytosine. Our results show a striking contrast in the genomic distributions of 6mA and 5-methylcytosine and reinforce a distinct role for 6mA as a gene-expression-associated epigenomic mark in eukaryotes.
59 BASIC BIOLOGICAL SCIENCES↗
Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein
No vaccine exists against group A Streptococcus (GAS), a leading cause of worldwide morbidity and mortality. A severe hurdle is the hypervariability of its major antigen, the M protein, with >200 different M types known. Neutralizing antibodies typically recognize M protein hypervariable regions (HVRs) and confer narrow protection. In stark contrast, human C4b-binding protein (C4BP), which is recruited to the GAS surface to block phagocytic killing, interacts with a remarkably large number of M protein HVRs (apparently ~90%). Such broad recognition is rare, and we discovered a unique mechanism for this through the structure determination of four sequence-diverse M proteins in complexes with C4BP. The structures revealed a uniform and tolerant ‘reading head’ in C4BP, which detected conserved sequence patterns hidden within hypervariability. Our results open up possibilities for rational therapies that target the M–C4BP interaction, and also inform a path towards vaccine design.
59 BASIC BIOLOGICAL SCIENCES↗
Sequential slip transfer of mixed-character dislocations across Σ3 coherent twin boundary in FCC metals: a concurrent atomistic-continuum study
Sequential slip transfer across grain boundaries (GB) has an important role in size-dependent propagation of plastic deformation in polycrystalline metals. For example, the Hall–Petch effect, which states that a smaller average grain size results in a higher yield stress, can be rationalised in terms of dislocation pile-ups against GBs. In spite of extensive studies in modelling individual phases and grains using atomistic simulations, well-accepted criteria of slip transfer across GBs are still lacking, as well as models of predicting irreversible GB structure evolution. Slip transfer is inherently multiscale since both the atomic structure of the boundary and the long-range fields of the dislocation pile-up come into play. In this work, concurrent atomistic-continuum simulations are performed to study sequential slip transfer of a series of curved dislocations from a given pile-up on Σ3 coherent twin boundary (CTB) in Cu and Al, with dominant leading screw character at the site of interaction. A Frank-Read source is employed to nucleate dislocations continuously. It is found that subject to a shear stress of 1.2 GPa, screw dislocations transfer into the twinned grain in Cu, but glide on the twin boundary plane in Al. Moreover, four dislocation/CTB interaction modes are identified in Al, which are affected by (1) applied shear stress, (2) dislocation line length, and (3) dislocation line curvature. Our results elucidate the discrepancies between atomistic simulations and experimental observations of dislocation-GB reactions and highlight the importance of directly modeling sequential dislocation slip transfer reactions using fully 3D models.
36 MATERIALS SCIENCE↗
Erratum: Computational understanding of Li-ion batteries
Correction to: npj Computational Materials (2016) 2, 16002; doi:10.1038/npjcompumats.2016.2; published online 18 March 2016. Since the online publication of the above article, it has been noted that an acknowledgement section should have been included and the text should read: ‘This work was supported primarily by the U.S. Department of Energy (DOE) under Contract No. DE-FG02-96ER45571.’ This error has been corrected in the PDF and HTML versions of the article.
25 ENERGY STORAGE↗
Recognition of microbial glycans by human intelectin-1
The glycans displayed on mammalian cells can differ markedly from those on microbes. Such differences could, in principle, be 'read' by carbohydrate-binding proteins, or lectins. In this paper, we used glycan microarrays to show that human intelectin-1 (hIntL-1) does not bind known human glycan epitopes but does interact with multiple glycan epitopes found exclusively on microbes: β-linked D-galactofuranose (β-Galf), D-phosphoglycerol–modified glycans, heptoses, D-glycero-D-talo-oct-2-ulosonic acid (KO) and 3-deoxy-D-manno-oct-2-ulosonic acid (KDO). The 1.6-Å-resolution crystal structure of hIntL-1 complexed with β-Galf revealed that hIntL-1 uses a bound calcium ion to coordinate terminal exocyclic 1,2-diols. N-acetylneuraminic acid (Neu5Ac), a sialic acid widespread in human glycans, has an exocyclic 1,2-diol but does not bind hIntL-1, probably owing to unfavorable steric and electronic effects. hIntL-1 marks only Streptococcus pneumoniae serotypes that display surface glycans with terminal 1,2-diol groups. Finally, this ligand selectivity suggests that hIntL-1 functions in microbial surveillance.
60 APPLIED LIFE SCIENCES↗
Position-dependent termination and widespread obligatory frameshifting in Euplotes translation
The ribosome can change its reading frame during translation in a process known as programmed ribosomal frameshifting. These rare events are supported by complex mRNA signals. However, we found that the ciliates Euplotes crassus and Euplotes focardii exhibit widespread frameshifting at stop codons. 47 different codons preceding stop signals resulted in either +1 or +2 frameshifts, and +1 frameshifting at AAA was the most frequent. The frameshifts showed unusual plasticity and rapid evolution, and had little influence on translation rates. The proximity of a stop codon to the 3' mRNA end, rather than its occurrence or sequence context, appeared to designate termination. Thus, a ‘stop codon’ is not a sufficient signal for translation termination, and the default function of stop codons in Euplotes is frameshifting, whereas termination is specific to certain mRNA positions and probably requires additional factors.
59 BASIC BIOLOGICAL SCIENCES↗
An all optical approach for comprehensive in-operando analysis of radiative and nonradiative recombination processes in GaAs double heterostructures
We demonstrate an all optical approach that can surprisingly offer the possibility of yielding much more information than one would expect, pertinent to the carrier recombination dynamics via both radiative and nonradiative processes when only one dominant deep defect level is present in a semiconductor material. By applying a band-defect state coupling model that explicitly treats the inter-band radiative recombination and Shockley–Read–Hall (SRH) recombination via the deep defect states on an equal footing for any defect center occupation fraction, and analyzing photoluminescence (PL) as a function of excitation density over a wide range of the excitation density (e.g., 5–6 orders in magnitude), in conjunction with Raman measurements of the LO-phonon plasmon (LOPP) coupled mode, nearly all of the key parameters relevant to the recombination processes can be obtained. They include internal quantum efficiency (IQE), minority and majority carrier density, inter-band radiative recombination rate (W r ), minority carrier nonradiative recombination rate (W nr ), defect center occupation fraction (f), defect center density (N t ), and minority and majority carrier capture cross-sections (σ t and σ tM ). While some of this information is thought to be obtainable optically, such as IQE and the W r /W nr ratio, most of the other parameters are generally considered to be attainable only through electrical techniques, such as current-voltage (I-V) characteristics and deep level transient spectroscopy (DLTS). Following a procedure developed herein, this approach has been successfully applied to three GaAs double-heterostructures that exhibit two distinctly different nonradiative recombination characteristics. The method greatly enhances the usefulness of the simple PL technique to an unprecedented level, facilitating comprehensive material and device characterization without the need for any device processing.
14 SOLAR ENERGY↗