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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

A novel mathematical method for disclosing oscillations ingene transcription: a comparative study

Circadian rhythmicity, the 24-hour cycle responsive to light and dark, is determined by periodic oscillations in gene transcription. This phenomenon has broad ramifications in physiologic function. Recent work has disclosed more cycles in gene transcription, and to the uncovering of these we apply a novel signal processing methodology known as the pencil method and compare it to conventional parametric, nonparametric, and statistical methods. Methods: In order to assess periodicity of gene expression over time, we analyzed a database derived from livers of mice entrained to a 12-hour light/12-hour dark cycle. We also analyzed artificially generated signals to identify differences between the pencil decomposition and other alternative methods.\n\nResultsThe pencil decomposition revealed hitherto-unsuspected oscillations in gene transcription with 12-hour periodicity. The pencil method was robust in detecting the 24-hour circadian cycle that was known to exist, as well as confirming the existence of shorter-period oscillations. A key consequence of this approach is that orthogonality of the different oscillatory components can be demonstrated. thus indicating a biological independence of these oscillations, that has been subsequently confirmed empirically by knocking out the gene responsible for the 24-hour clock.\n\nConclusionSystem identification techniques can be applied to biological systems and can uncover important characteristics that may elude visual inspection of the data. Significance: The pencil method provides new insights on the essence of gene expression and discloses a wide variety of oscillations in addition to the well-studied circadian pattern. This insight opens the door to the study of novel mechanisms by which oscillatory gene expression signals exert their regulatory effect on cells to influence human diseases.

cell biology↗

bioRxiv2017

Partitioning and Enhanced Self-Assembly of Actin in Polypeptide Coacervates

Biomolecules exist and function in cellular micro-environments that control their spatial organization, local concentration and biochemical reactivity. Due to the complexity of native cytoplasm, the development of artificial bioreactors and cellular mimics to compartmentalize, concentrate and control the local physicochemical properties is of great interest. Here, we employ self-assembling polypeptide coacervates to explore the partitioning of the ubiquitous cytoskeletal protein actin into liquid polymer-rich droplets. We find that actin spontaneously partitions into coacervate droplets and is enriched by up to {approx}30-fold. Actin polymerizes into micrometer-long filaments and, in contrast to the globular protein BSA, these filaments localize predominately to the droplet periphery. We observe up to a 50-fold enhancement in the actin filament assembly rate inside coacervate droplets, consistent with the enrichment of actin within the coacervate phase. Together these results suggest that coacervates can serve as a versatile platform in which to localize and enrich biomolecules to study their reactivity in physiological environments.\n\nSIGNIFICANCE STATEMENTLiving cells harbor many protein-rich membrane-less organelles, the biological functions of which are defined by compartment composition and properties. Significant differences between the physico-chemical properties of these crowded compartments and the dilute solutions in which biochemical reactions are traditionally studied pose a major challenge for understanding regulation of organelle composition and component activity. Here, we report the spontaneous partitioning and accelerated polymerization of the cytoskeletal protein actin inside model polypeptide coacervates as a proof-of-concept demonstration of coacervates as bioreactors for studying biomolecular reactions in cell-like environments. Our work introduces exciting avenues for the use of synthetic polymers to control the physical and biological properties of bioreactors in vitro, enabling studies of biochemical reactions in cell-like micro-environments.

biophysics↗

bioRxiv2017

Engineering Cell Sensing and Responses Using a GPCR-Coupled CRISPR-Cas System

G-protein coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes, and detects a wide array of physiological cues in the human body. We describe a new molecular device that couples CRISPR-Cas9 programmed genome regulation to natural and synthetic extracellular signals via GPCRs. The design of our synthetic device, named CRISPR ChaCha, displays superior performance over an architecture proposed by the previously reported Tango system. Using a parsimonious mathematical model and gene-reporter assays, we find that CRISPR ChaCha can recruit and activate multiple Cas9 molecules for each GPCR molecule. We also characterize key molecular features that modulate CRISPR ChaCha performance. We adopt the design to diverse GPCRs that sense synthetic and natural ligands including chemokines, mitogens, and fatty acids, and observe efficient conversion of signals to customizable genetic programs in mammalian cells, including regulation of endogenous genes. The new class of CRISPR-coupled GPCRs provides a robust and efficient platform for engineering cells with novel behaviors in response to the diverse GPCR ligand repertoire.

synthetic biology↗

bioRxiv2017

A conserved homo-dimerization interface in human IFIT1 provides insights into IFIT interactome assembly

The Interferon-Induced Proteins with Tetratricopeptide Repeats (IFITs) are a group of potently expressed Interferon Stimulated Genes that mediate antiviral innate immunity. Previous studies have revealed that most IFITs partake in higher order structures, potentially as part of an IFIT interactome that results in viral inhibition. Recent crystal structures of a mutated, monomeric form of IFIT1 revealed the molecular basis of how it recognizes non-self, capped viral mRNAs to selectively inhibit their translation. However, wild-type IFIT1 forms dimers in solution and the role of dimerization was not examined in detail. Here we present a structural and biochemical analysis of wild-type IFIT1 in complex with capped and uncapped RNA. Wild-type IFIT1 forms an antiparallel, elongated dimer that is in stark contrast to the domain-swapped, parallel dimer found in IFIT2. Dimerization takes place through a small, C-terminal interface that is evolutionarily conserved in IFIT1 and IFIT1B proteins. The interface is modular and can be grafted onto IFIT5, which is natively monomeric, to induce dimerization. Mutational analysis of this interface showed that homo-dimerization is not required for full RNA binding or translational inhibition by IFIT1. Sedimentation velocity analytical ultracentrifugation measurements demonstrated a reversible monomer-dimer equilibrium, suggesting that dimerization is of low affinity and could play a role under physiological concentrations, possibly in regulating IFIT interactome assembly. Finally, conformational changes in IFIT1 that occur upon RNA binding provide insight into how RNA enters its binding site in solution.

biochemistry↗

bioRxiv2017

Effects of LSD on music-evoked brain activity

Music is a highly dynamic stimulus, and consists of distinct acoustic features, such as pitch, rhythm and timbre. Neuroimaging studies highlight a hierarchy of brain networks involved in music perception. Psychedelic drugs such as lysergic acid diethylamide (LSD) temporary disintegrate the normal hierarchy of brain functioning, and produce profound subjective effects, including enhanced music-evoked emotion. The primary objective of this study was to investigate the acute effects of LSD on music-evoked brain-activity under naturalistic music listening conditions. 16 healthy participants were enrolled in magnetic resonance imaging (fMRI) while listening to a 7-minute music piece under eyes-closed conditions on two separate visits (LSD (75 mcg) and placebo). Dynamic time courses for acoustic features were extracted from the music excerpts, and were entered into subject-level fMRI analyses as regressors of interest. Differences between conditions were assessed at group level subsequently, and were related to changes in music-evoked emotions via correlation analyses. Psycho-physiological interactions (PPIs) were carried out to further interrogate underlying music-specific changes in functional connectivity under LSD. Results showed pronounced cortical and subcortical changes in music-evoked brain activity under LSD. Most notable changes in brain activity and connectivity were associated with the component timbral complexity, representing the complexity of the musics spectral distribution, and these occurred in brain networks previously identified for music-perception and music-evoked emotion, and showed an association with enhanced music-evoked feelings of wonder under LSD. The findings shed light on how the brain processes music under LSD, and provide a neurobiological basis for the usefulness of music in psychedelic therapy.

neuroscience↗

bioRxiv2017

Predator-secreted sulfolipids induce fear-like defense responses in C. elegans

Animals respond to predators by altering their behavior and physiological states, but the underlying signaling mechanisms are poorly understood. Using the interactions between Caenorhabditis elegans and its predator, Pristionchus pacificus, we show that neuronal perception by C. elegans of a predator-specific molecular signature induces instantaneous escape behavior and a prolonged reduction in oviposition. Chemical analysis revealed this predator-specific signature to consist of a class of sulfolipids, produced by a biochemical pathway required for developing predacious behavior and specifically induced by starvation. These sulfolipids are detected by four pairs of C. elegans amphid sensory neurons that act redundantly and recruit cyclic nucleotide-gated (CNG) or transient receptor potential (TRP) channels to drive both escape and reduced oviposition. Specific abolishment of predator-evoked C. elegans responses by the anti-anxiety drug sertraline as well as functional homology of the delineated signaling pathways suggests a conserved or convergent strategy for managing predator threats.

neuroscience↗

bioRxiv2017

Cyclic electron flow in Chlamydomonas reinhardtii

Cyclic electron flow (CEF), one of the major alternative electron transport pathways to the primary linear electron flow (LEF) in chloroplasts has been discovered in the middle of the last century. It is defined as a return of the reductants from the acceptor side of the Photosystem I (PSI) to the pool of its donors via the cytochrome b6f, and has proven essential for photosynthesis. However, despite many efforts aimed at its characterisation, the pathway and regulation of CEF remain equivocal, and its physiological significance remains to be properly defined. Here we use novel spectroscopic approaches to measure CEF in transitory conditions in the green alga Chlamydomonas reinhardtii. We show that CEF operates at the same maximal rate regardless of the oxygen concentration, and that the latter influences LEF, rather than CEF in vivo, which questions the recent hypotheses about the CEF supercomplex formation. We further reveal that the pathways proposed for CEF in the literature are inconsistent with the kinetic information provided by our measurements. We finally provide cues on the regulation of CEF by light.

plant biology↗

bioRxiv2017

Analysis of hippocampal transcriptomic responses to technical and biological perturbations

Cost-effective next-generation sequencing has made unbiased gene expression analysis possible. Single-neuron gene expression studies may be especially important for understanding nervous system structure and function because of the neuron-specific functionality and plasticity that defines functional neural circuits. Cellular dissociation is a prerequisite technical manipulation for single-cell and single cell-population studies, but the extent to which the cellular dissociation process cells affects neural gene expression has not been determined, nor has it been determined how gene expression is altered by the stress that accompanies many of the behavioral manipulations that are required to study learning and memory and other cognitive functions. Here, we determined to which extent cellular dissociation-induced changes in hippocampal gene expression might confound studies on the behavioral and physiological functions of the hippocampus. We processed tissue punch samples from the dentate gyrus (DG), CA3, and CA1 hippocampus subfields using either a tissue homogenization protocol or a cellular dissociation protocol in preparation for RNA sequencing analysis to evaluate the impact of the tissue preparation. Then, we evaluated the effect of stressful experience and cognitive training on hippocampus subfield specific gene expression and determined to which extent these response overlap with the cellular dissociation response. Finally, we assessed the extent to which the subfield-specific gene expression patterns are consistent with those identified in a recently published hippocampus subfield-specific gene expression database. We report substantial differences in baseline subfield-specific gene expression, that 1% of the hippocampal transcriptome is altered by the process of cellular dissociation, that an even weaker alteration is detected 24 h after stressful experience, and that while these alterations are largely distinct from the subfield specific response of the hippocampus transcriptome to cognitive training, there is nonetheless some important confounding overlap. These findings of the concordant and discordant effects of technical and behavioral manipulations should inform the design of future neural transcriptome studies and thus facilitate a more comprehensive understanding of hippocampal function.

neuroscience↗

bioRxiv2017

Elevated ozone reduces photosynthetic carbon gain by accelerating leaf senescence of inbred and hybrid maize in a genotype-specific manner

Exposure to elevated tropospheric ozone concentration ([O3]) accelerates leaf senescence in many C3 crops. However, the effects of elevated [O3] on C4 crops including maize (Zea mays L.) are poorly understood in terms of physiological mechanism and genetic variation in sensitivity. Using Free Air gas Concentration Enrichment (FACE), we investigated the photosynthetic response of 18 diverse maize inbred and hybrid lines to season-long exposure to elevated [O3] (~100 nL L-1) in the field. Gas exchange was measured on the leaf subtending the ear throughout the grain filling period. On average over the lifetime of the leaf, elevated [O3] led to reductions in photosynthetic CO2 assimilation of both inbred (-22%) and hybrid (-33%) genotypes. There was significant variation among both inbred and hybrid lines in the sensitivity of photosynthesis to elevated [O3], with some lines showing no change in photosynthesis at elevated [O3]. Based on analysis of inbred line B73, the reduced CO2 assimilation at elevated [O3] was associated with accelerated senescence decreasing photosynthetic capacity, and not altered stomatal limitation. These findings across diverse maize genotypes could advance the development of more ozone tolerant maize, and provide experimental data for parameterization and validation of studies modeling how O3 impacts crop performance.

plant biology↗

bioRxiv2017

Interplay between mitochondria and diet mediates pathogen and stress resistance in C. elegans

Diet is a crucial determinant of organismal biology. Here we demonstrate the dramatic impact of a subtle shift in diet on the ability of Caenorhabditis elegans to survive pathogenic or abiotic stress. Interestingly, this shift occurs independently of canonical host defense pathways, arising instead from improvements in mitochondrial health. Using a variety of assays, we reveal that the most common C. elegans food source (E. coli OP50) results in a vitamin B12 deficiency that compromises mitochondrial homeostasis. Increasing B12 supply by feeding on E. coli HT115 or by supplementing bacterial media with methylcobalamin restored mitochondrial function, even if the bacteria were dead. B12 supplementation also efficiently increased host health without adversely affecting lifespan. Our study forges a molecular link between a dietary deficiency (nutrition/microbiota) and a physiological consequence (host sensitivity), using the host-microbiota-diet framework. The ubiquity of B12 deficiency (~10-40% of US adults) highlights the importance of our findings.

molecular biology↗

bioRxiv2017

A convergent depression vulnerability pathway encoded by emergent spatiotemporal dynamics

Fluctuations in brain local field potential (LFP) oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these LFP oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional processes at the network level. Here we use machine learning to integrate LFP activity acquired concurrently from seven cortical and subcortical brain regions into an analytical model that predicts the emergence of depression-related behavioral dysfunction across individual mice subjected to chronic social defeat stress. We uncover a spatiotemporal dynamic network in which activity originates in prefrontal cortex (PFC) and nucleus accumbens (NAc, ventral striatum), relays through amygdala and ventral tegmental area (VTA), and converges in ventral hippocampus (VHip). The activity of this network correlates with acute threat responses and brain-wide cellular firing, and it is enhanced in three independent molecular-, physiological-, and behavioral-based models of depression vulnerability. Finally, we use two antidepressant manipulations to demonstrate that this vulnerability network is biologically distinct from the networks that signal behavioral dysfunction after stress. Thus, corticostriatal to VHip-directed spatiotemporal dynamics organized at the network level are a novel convergent depression vulnerability pathway.

neuroscience↗

bioRxiv2017

SWELL1 is a glucose sensor required for β-cell excitability and insulin secretion

Insulin secretion from the pancreatic {beta}-cell initiated by activation of voltage-gated Ca2+ channels (VGCC) to trigger Ca2+-mediated insulin vesicle fusion with the {beta}-cell plasma membrane. The firing of VGCC depends on the {beta}-cell membrane potential, which is in turn mediated by the balance of depolarizing (excitatory) and hyperpolarizing (inhibitory) ionic currents1-3. While much attention has focused on inhibitory potassium currents4-10 there is little knowledge about the excitatory currents required to depolarize the {beta}-cell, including the molecular identity of these excitatory currents3. Here we show that SWELL1 (LRRC8a) mediates a swell-activated, depolarizing chloride current (ICl,SWELL) in {beta}-cells. Hypotonic and glucose-stimulated {beta}-cell swelling activates SWELL1-mediated ICl,SWELL and this is required for both glucose-stimulated and hypotonic swell-mediated activation of VGCC-dependent intracellular calcium signaling in {beta}-cells. SWELL1 KO MIN6 cells and {beta}-cell targeted SWELL1 KO murine islets exhibit significantly impaired glucose-stimulated insulin secretion, with preserved insulin content in vitro. Tamoxifen-inducible {beta}-cell targeted SWELL1 KO mice have normal fasting insulin levels but display markedly impaired glucose-stimulated insulin secretion. Our results reveal a physiological role for SWELL1 as a glucose sensor - linking glucose-mediated {beta}-cell swelling to SWELL1-dependent activation of VGCC-triggered calcium signaling, and highlights SWELL1-mediated \"swell-secretion\" coupling as required for glucose-stimulated insulin secretion.

cell biology↗

bioRxiv2017

High-quality genome assemblies uncover caste-specific long non-coding RNAs in ants

Ants are an emerging model system for neuroepigenetics, as embryos with virtually identical genomes develop into different adult castes that display strikingly different physiology, morphology, and behavior. Although a number of ant genomes have been sequenced to date, their draft quality is an obstacle to sophisticated analyses of epigenetic gene regulation. Using long reads generated with Pacific Biosystem single molecule real time sequencing, we have reassembled de novo high-quality genomes for two ant species: Camponotus floridanus and Harpegnathos saltator. The long reads allowed us to span large repetitive regions and join sequences previously found in separate scaffolds, leading to comprehensive and accurate protein-coding annotations that facilitated the identification of a Gp-9-like gene as differentially expressed in Harpegnathos castes. The new assemblies also enabled us to annotate long non-coding RNAs for the first time in ants, revealing several that were specifically expressed during Harpegnathos development and in the brains of different castes. These upgraded genomes, along with the new coding and non-coding annotations, will aid future efforts to identify epigenetic mechanisms of phenotypic and behavioral plasticity in ants.

genomics↗

bioRxiv2017

A cerebellar mechanism for learning prior distributions of time intervals

Knowledge about the statistical regularities of the world is essential for cognitive and sensorimotor function. In the domain of timing, prior statistics are crucial for optimal prediction, adaptation and planning. Where and how the nervous system encodes temporal statistics, however, is not known. Deriving from physiological and anatomical evidence for cerebellar learning, we develop a computational model that demonstrates how the cerebellum could learn prior distributions of time intervals and support Bayesian temporal estimation. The model shows that salient features observed in human Bayesian time interval estimates can be readily captured by learning in the cerebellar cortex and circuit level computations in the cerebellar deep nuclei.

neuroscience↗

bioRxiv2017

Systematic identification of novel regulatory interactions controlling biofilm formation in the bacterium Escherichia coli

Here, we investigated novel interactions of three global regulators of the network that controls biofilm formation in the model bacterium Escherichia coli using computational network analysis, an in vivo reporter assay and physiological validation experiments. We were able to map critical nodes that govern planktonic to biofilm transition and identify 8 new regulatory interactions for CRP, IHF or Fis responsible for the control of the promoters of rpoS, rpoE, flhD, fliA, csgD and yeaJ. Additionally, an in vivo promoter reporter assay and motility analysis revealed a key role for IHF as a repressor of cell motility through the control of FliA sigma factor expression. This investigation of first stage and mature biofilm formation indicates that biofilm structure is strongly affected by IHF and Fis, while CRP seems to provide a fine-tuning mechanism. Taken together, the analysis presented here shows the utility of combining computational and experimental approaches to generate a deeper understanding of the biofilm formation process in bacteria.

microbiology↗

bioRxiv2017

Activation of Somatostatin Inhibitory Neurons by Lypd6-nAChRα2 System Restores Juvenile-like Plasticity in Adult Visual Cortex

The limitation of plasticity in the adult brain impedes functional recovery later in life from brain injury or disease. This pressing clinical issue may be resolved by enhancing plasticity in the adult brain. One strategy for triggering robust plasticity in adulthood is to reproduce one of the hallmark physiological events of experience-dependent plasticity observed during the juvenile critical period - rapidly reduce the activity of parvalbumin (PV)-expressing interneurons and disinhibit local excitatory neurons. This may be achieved through enhancement of local inhibitory inputs, particularly those of somatostatin (SST)-expressing interneurons. However, to date the means for manipulating SST interneurons for enhancing cortical plasticity in the adult brain are not known. We show that SST interneuron-selective overexpression of Lypd6, an endogenous nicotinic signaling modulator, enhances ocular dominance plasticity in the adult primary visual cortex (V1). Lypd6 overexpression mediates a rapid experience-dependent increase in the visually evoked activity of SST interneurons as well as a simultaneous reduction in PV interneuron activity and disinhibition of excitatory neurons. Recapitulating this transient activation of SST interneurons using chemogenetics similarly enhanced V1 plasticity. Notably, we show that SST-selective Lypd6 overexpression restores visual acuity in amblyopic mice that underwent early long-term monocular deprivation. Our data in both male and female mice reveal selective modulation of SST interneurons and a putative downstream circuit mechanism as an effective method for enhancing experience-dependent cortical plasticity as well as functional recovery in adulthood. Significance StatementThe decline of cortical plasticity after closure of juvenile critical period consolidates neural circuits and behavior, but this limits functional recovery from brain diseases and dysfunctions in later life. Here we show that activation of cortical SST interneurons by Lypd6, an endogenous modulator of nicotinic acetylcholine receptors (nAChRs), enhances experience-dependent plasticity and recovery from amblyopia in adulthood. This manipulation triggers rapid reduction of PV interneuron activity and disinhibition of excitatory neurons, which are known hallmarks of cortical plasticity during juvenile critical periods. Our study demonstrates modulation of SST interneurons by Lypd6 to achieve robust levels of cortical plasticity in the adult brain and may provide promising targets for restoring brain function in the event of brain trauma or disease.

neuroscience↗

bioRxiv2017

Cofilin Drives Rapid Turnover and Fluidization of Entangled F-actin

The shape of most animal cells is controlled by the actin cortex, a thin, isotropic network of dynamic actin filaments (F-actin) situated just beneath the plasma membrane. The cortex is held far from equilibrium by both active stresses and turnover: Myosin-II molecular motors drive deformations required for cell division, migration, and tissue morphogenesis, while turnover of the molecular components of the actin cortex relax stress and facilitate network reorganization. While many aspects of F-actin network viscoelasticity are well-characterized in the presence and absence of motor activity, a mechanistic understanding of how non-equilibrium actin turnover contributes to stress relaxation is still lacking. To address this, we developed a reconstituted in vitro system wherein the steady-state length and turnover rate of F-actin in entangled solutions are controlled by the actin regulatory proteins cofilin, profilin, and formin, which sever, recycle, and nucleate filaments, respectively. Cofilin-mediated severing accelerates the turnover and spatial reorganization of F-actin, without significant changes to filament length. Microrheology measurements demonstrate that cofilin-mediated severing is a single-timescale mode of stress relaxation that tunes the low-frequency viscosity over two orders of magnitude. These findings serve as the foundation for understanding the mechanics of more physiological F-actin networks with turnover, and inform an updated microscopic model of single-filament turnover. They also demonstrate that polymer activity, in the form of ATP hydrolysis on F-actin coupled to nucleotide-dependent cofilin binding, is sufficient to generate a form of active matter wherein asymmetric filament disassembly preserves filament number in spite of sustained severing.\n\nSignificance StatementWhen an animal cell moves or divides, a disordered network of actin filaments (F-actin) plays a central role in controlling the resulting changes in cell shape. While it is known that continual turnover of F-actin by cofilin-mediated severing aids in reorganization of the cellular cytoskeleton, it is unclear how the turnover of structural elements alters the mechanical properties of the network. Here we show that severing of F-actin by cofilin results in a stress relaxation mechanism in entangled solutions characterized by a single-timescale set by the severing rate. Additionally, we identify ATP hydrolysis and nucleotide-dependent cofilin binding as sufficient ingredients to generate a non-equilibrium steady-state in which asymmetric F-actin disassembly preserves filament number in spite of sustained severing.

biophysics↗

bioRxiv2017

Voltage-gating of mechanosensitive PIEZO channels

Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms. Here we show that, in addition to mechanical stimuli, PIEZO channels are also powerfully modulated by voltage and can even switch to a purely voltage gated mode. Mutations that cause human diseases such as Xerocytosis profoundly shift voltage sensitivity of PIEZO1 channels towards the resting membrane potential and strongly promote pure voltage gating. Our data may be explained by the presence of an inactivation gate in the pore, the opening of which is promoted by outward permeation. Invertebrate (fly) and vertebrate (fish) PIEZO proteins are also voltage sensitive but voltage gating is a much more prominent feature of these older channels. We propose that the voltage sensitivity of PIEZO channels is a deep property co-opted to add a regulatory mechanism for PIEZO activation in widely different cellular contexts.

neuroscience↗