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bioRxiv2017

Modeling the schizophrenias: subunit-specific NMDAR antagonism dissociates oscillatory signatures of frontal hypofunction and hippocampal hyperfunction

NMDAR antagonism alters mesolimbic, hippocampal, and cortical function, acutely reproducing the positive, cognitive, and negative symptoms of schizophrenia. These physiological and behavioral effects may depend differentially on NMDAR subtype-and region-specific effects. The dramatic electrophysiological signatures of NMDAR blockade in rodents include potentiated high frequency oscillations (HFOs, ~140 Hz), likely generated in mesolimbic structures, and increased HFO phase-amplitude coupling (PAC), a phenomenon related to goal-directed behavior and dopaminergic tone. This study examined the impact of subtype-specific NMDAR antagonism on HFOs and PAC. We found that positive-symptom-associated NR2A-preferring antagonism (NVP-AAM077), but not NR2B-specific antagonism (Ro25-6985) or saline control, replicated increases in HFO power seen with nonspecific antagonism (MK-801). However, PAC following NR2A-preferring antagonism was distinct from all other conditions. While{theta} -HFO PAC was prominent or potentiated in other conditions, NVP-AAM077 increased{delta} -HFO PAC and decreased{theta} -HFO PAC. Furthermore, active wake epochs exhibiting narrowband frontal{delta} oscillations, and not broadband sleep-associated{delta} , selectively exhibited{delta} -HFO coupling, while paradoxical sleep epochs having a high CA1{theta} to frontal{delta} ratio selectively exhibited{theta} -HFO coupling. Our results suggest: (1) NR2A-preferring antagonism induces oscillopathies re[fl]ecting frontal hyperfunction and hippocampal hypofunction; and (2) HFO PAC indexes cortical vs. hippocampal control of mesolimbic circuits.

neuroscience↗

bioRxiv2017

Reconstructing the Molecular Life History of Gliomas

At the time of clinical presentation, the very heterogeneous group of pediatric and adult gliomas carry a wide range of diverse somatic genomic alterations. These include chromosome-sized gains and losses, focal amplification and deletions, rearrangements resulting in transcript fusions, small insertions/deletions, and point mutations. Tumor cells pay a penalty for maintaining these abnormalities which therefore must provide cells with a competitive advantage to become engrained into the glioma genome. Here, we propose a model for gliomagenesis consisting of five consecutive phases that glioma cells have traversed prior to diagnosis. Tumor growth is repressed by activated DNA damage response pathways and dysfunctional telomeres in physiological conditions. Disruption of the p16-RB-p53 pathway and the acquisition of a telomere maintenance mechanism can bypass these bottlenecks. We relate somatic alterations to each of these steps, in order to reconstruct the life history of glioma. Understanding the story that each glioma tells at presentation may facilitate the design of novel, more effective therapeutic approaches.\n\nKey ConceptsGlioma initiating event: The first event that initiates the clonal expansion of cells\n\nOncogene-induced senescence: Durable growth arrest triggered by continued oncogene exposure\n\nReplicative senescence: Durable growth arrest triggered via telomere dysfunction and activated DNA damage pathways\n\nCrisis: Widespread cell death triggered via telomere dysfunction\n\nSenescence bypass event: Any molecular alteration that bypasses or suppresses oncogene-induced senescence\n\nSenescence-associated secretory phenotype (SASP): Senescent cells secrete various immunogenic cytokines, growth factors and proteases into the microenvironment\n\nFunctional redundancy: Used to describe two or more genomic changes that provide overlapping functional effect\n\nNeutral evolution: changes due to stochastic allelic variation that do not affect fitness\n\nSelective sweep: The elimination of genetic variation following strong positive selection effectively reducing the tumor to a single clone\n\nClonal event: Somatic mutation or copy number event that is conserved across all tumor cells\n\nSubclonal event: Somatic mutation or copy number event that is only present in a subset (subclone) of tumor cells\n\nChromothripsis: A punctuated shattering of genomic DNA\n\nKataegis: Clustered regions of hypermutation\n\nPolyploidization: The multiplication of chromosome content in a cell\n\nBreakage fusion bridge (BFB) cycle: Cyclic fusion of uncapped telomeres, bridge formation during anaphase and subsequent breakage leading to unequal inheritance of DNA\n\nDicentric chromosome: Two fused chromosomes span across the mitotic spindle in anaphase, called dicentric because it has two centromeres\n\nDouble minute (DM) chromosome: Extra-chromosomal circular DNA segment lacking centromere(s) and telomeres\n\nImmortalization event: The last straw in the immortalization process that directly leads to telomere stabilization

cancer biology↗

bioRxiv2018

Neutralizing Gatad2a-Chd4-Mbd3 Axis within the NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency

The Nucleosome Remodeling and Deacytelase (NuRD) complex is a co-repressive complex involved in many pathological and physiological processes in the cell. Previous studies have identified one of its components, Mbd3, as a potent inhibitor for reprogramming of somatic cells to pluripotency. Following OSKM induction, early and partial depletion of Mbd3 protein followed by applying naive ground-state pluripotency conditions, results in a highly efficient and near-deterministic generation of mouse iPS cells. Increasing evidence indicates that the NuRD complex assumes multiple mutually exclusive protein complexes, and it remains unclear whether the deterministic iPSC phenotype is the result of a specific NuRD sub complex. Since complete ablation of Mbd3 blocks somatic cell proliferation, here we aimed to identify alternative ways to block Mbd3-dependent NuRD activity by identifying additional functionally relevant components of the Mbd3/NuRD complex during early stages of reprogramming. We identified Gatad2a (also known as P66), a relatively uncharacterized NuRD-specific subunit, whose complete deletion does not impact somatic cell proliferation, yet specifically disrupts Mbd3/NuRD repressive activity on the pluripotency circuit during both stem cell differentiation and reprogramming to pluripotency. Complete ablation of Gatad2a in somatic cells, but not Gatad2b, results in a deterministic naive iPSC reprogramming where up to 100% of donor somatic cells successfully complete the process within 8 days. Genetic and biochemical analysis established a distinct sub-complex within the NuRD complex (Gatad2a-Chd4-Mbd3) as the functional and biochemical axis blocking reestablishment of murine naive pluripotency. Disassembly of this axis by depletion of Gatad2a, results in resistance to conditions promoting exit of naive pluripotency and delays differentiation. We further highlight context- and posttranslational dependent modifications of the NuRD complex affecting its interactions and assembly in different cell states. Collectively, our work unveils the distinct functionality, composition and interactions of Gatad2a-Chd4-Mbd3/NuRD subcomplex during the resolution and establishment of mouse naive pluripotency.

developmental biology↗

bioRxiv2017

A common pattern of DNase-I footprinting throughout the human mtDNA unveils clues for a chromatin-like organization

Human mitochondrial DNA (mtDNA) is believed to lack chromatin and histones. Instead, it is coated solely by the transcription factor TFAM, which binds the mtDNA without sequence specificity and packs it into a bacterial-like nucleoid in a dose-dependent fashion. We asked whether mtDNA packaging is more regulated than once thought. As a first step to address this question, we analyzed mtDNA DNase-I-seq experiments in 324 different human cell types and found, for the first time, a pattern of 29 Genomic footprinting (DGF) sites throughout the mtDNA shared by [~]90% of the tested samples. Low SNP density at the DGF sites, and their conservation in mouse DNase-seq experiments, reflect strong selective constraints. Co-localization of the DGFs with known mtDNA regulatory elements and with recently-discovered transcription pausing sites, suggest a role for such DGFs in mtDNA transcription. Altered mtDNA DGF pattern in IL-3 treated CD+34 cells offer first clue to their physiological importance. Taken together, human mtDNA has a conserved and regulated protein-DNA organization, which is likely involved in regulation of mtDNA gene expression.

genomics↗

bioRxiv2017

Age-related decline in behavioral discrimination of amplitude modulation frequencies compared to envelope-following responses

The ability to discriminate modulation frequencies is important for speech intelligibility because speech has amplitude and frequency modulations. Neurophysiological responses assessed by envelope following responses (EFRs) significantly decline at faster amplitude modulation frequencies (AMF) in older subjects. A typical assumption is that a decline in EFRs will necessarily result in corresponding perceptual deficits. To test this assumption, we investigated young and aged Fischer-344 rats behavioral AMF discrimination abilities and compared to their EFRs. A modified version of prepulse inhibition (PPI) of acoustic startle reflex (ASR) was used to obtain behavioral performance. A PPI trial contains pulses of sinusoidal AM (SAM) at 128 Hz presented sequentially, a SAM prepulse with different AMF and a startle-eliciting-stimulus. To account for hearing threshold shift or age-related synaptopathy, stimulus levels were presented at 10-dB lower or match to the aged peripheral neural activation (using auditory brainstem response wave I amplitude). When AMF differences and modulation depths were large, young and aged animals behavioral performances were comparable. Aged animals AMF discrimination abilities declined as the AMF difference or the modulation depth reduced, even compared to the young with peripheral matching. Young animals showed smaller relative decreases in EFRs with reduced modulation depths. The correlation of EFRs and AM perception was identified to be more consistent in young animals. The overall results revealed larger age-related deficits in behavioral perception compared to EFRs, suggesting additional factors that affect perception despite smaller degradation in neural responses. Hence, behavioral and physiological measurements are critical in unveiling a more complete picture on the auditory function.

neuroscience↗

bioRxiv2017

Synaptic co-transmission of acetylcholine and GABA regulates hippocampal states

The basal forebrain cholinergic system is widely assumed to control cortical functions via non-synaptic transmission of a single neurotransmitter, acetylcholine. Yet, using immune-electron tomographic, molecular anatomical, optogenetic and physiological techniques, we find that mouse hippocampal cholinergic terminals invariably establish synapses and their vesicles dock at synapses only. We demonstrate that these synapses do not co-release but co-transmit GABA and acetylcholine via different vesicles, whose release is triggered by distinct calcium channels. This co-transmission evokes fast composite postsynaptic potentials, which are mutually cross-regulated by presynaptic auto-receptors and display different short-term plasticity. The GABAergic component alone effectively suppresses hippocampal sharp wave-ripples and epileptiform activity. The synaptic nature of the forebrain cholinergic system with differentially regulated, fast, GABAergic and cholinergic co-transmission suggests a hitherto unrecognized level of synaptic control over cortical states. This novel model of hippocampal cholinergic neurotransmission could form the basis for alternative pharmacotherapies after cholinergic deinnervation seen in neurodegenerative disorders.\n\nSupplementary materials are attached after the main text.

neuroscience↗

bioRxiv2017

Gauss-power mixing distributions comprehensively describe stochastic variations in RNA-seq data

MotivationGene expression levels exhibit stochastic variations among genetically identical organisms under the same environmental conditions. In many recent transcriptome analyses based on RNA sequencing (RNA-seq), variations in gene expression levels among replicates were assumed to follow a negative binomial distribution although the physiological basis of this assumption remain unclear.\n\nResultsIn this study, RNA-seq data were obtained from Arabidopsis thaliana under eight conditions (21-27 replicates), and the characteristics of gene-dependent distribution profiles of gene expression levels were analyzed. For A. thaliana and Saccharomyces cerevisiae, the distribution profiles could be described by a Gauss-power mixing distribution derived from a simple model of a stochastic transcriptional network containing a feedback loop. The distribution profiles of gene expression levels were roughly classified as Gaussian, power law-like containing a long tail, and mixed. The fitting function predicted that gene expression levels with long-tailed distributions would be strongly influenced by feedback regulation. Thus, the features of gene expression levels are correlated with their functions, with the levels of essential genes tending to follow a Gaussian distribution and those of genes encoding nucleic acid-binding proteins and transcription factors exhibiting long-tailed distributions.\n\nAvailabilityFastq files of RNA-seq experiments were deposited into the DNA Data Bank of Japan Sequence Read Archive as accession no. DRA005887. Quantified expression data are available in supplementary information.\n\nContactawa@hiroshima-u.ac.jp\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2017

The Complex Simplicity of the Brittle Star Nervous System

Brittle stars (Ophiuroidea, Echinodermata) have been increasingly used in studies of animal behavior, locomotion, regeneration, physiology, and bioluminescence. The success of these studies directly depends on good working knowledge of ophiuroid nervous system. Here, we describe the arm nervous system at different levels of organization: microanatomy of the radial nerve cord and peripheral nerves, neural ultrastructure, and localization of different cell types using specific antibody markers. We standardize the nomenclature of nerves and ganglia and provide an anatomically accurate digital 3D model of the arm nervous system as a reference for future studies. Our results helped identify several general features characteristic to the adult echinoderm nervous system, including the extensive anatomical interconnections between the ectoneural and hyponeural components and neuroepithelial organization of the central nervous system with its supporting scaffold formed by radial glial cells. In addition, we provide further support to the notion that the echinoderm radial glia is a complex and diverse cell population. We also tested the suitability of a range of specific cell-type markers for studies of the brittle star nervous system and established that the radial glial cells are reliably labeled by the ERG1 antibodies, whereas the best neuronal markers are acetylated tubulin, ELAV and synaptotagmin B. The transcription factor Brn1/2/4, a marker of neuronal progenitors, is expressed not only in neurons, but also in a subpopulation of radial glia. For the first time, we describe putative ophiuroid proprioceptors associated with the hyponeural part of the central nervous system.

neuroscience↗

bioRxiv2017

Arabidopsis phenotyping through Geometric Morphometrics

In recent years, much technical progress has been done regarding plant phenotyping including the model species Arabidopsis thaliana. With automated, high-throughput platforms and the development of improved algorithms for the rosette segmentation task, it is now possible to massively extract reliable shape and size parameters for genetic, physiological and environmental studies. The development of low-cost phenotyping platforms and freeware resources make it possible to widely expand phenotypic analysis tools for Arabidopsis. However, objective descriptors of shape parameters that could be used independently of platform and segmentation software used are still lacking and shape descriptions still rely on ad hoc or even sometimes contradictory descriptors, which could make comparisons difficult and perhaps inaccurate. Modern geometric morphometrics is a family of methods in quantitative biology proposed to be the main source of data and analytical tools in the emerging field of phenomics studies. It has been used for taxonomists and paleontologists for decades and is now a mature discipline. By combining geometry, multivariate analysis and powerful statistical techniques, it offers the possibility to reproducibly and accurately account for shape variations amongst groups. Based on the location of homologous landmarks points over photographed or scanned specimens, these tools could identify the existence and degree of shape variation and measure them in standard units. Here, it is proposed a particular scheme of landmarks placement on Arabidopsis rosette images to study shape variation in the case study of viral infection processes. Several freeware-based geometric morphometric tools are applied in order to exemplify the usefulness of this approach to the study of phenotypes in this model plant. These methods are concisely presented and explained. Shape differences between controls and infected plants are quantified throughout the infectious process and visualized with the appealing graphs that are a hallmark of these techniques and render complex mathematical analysis simple outcomes to interpret. Quantitative comparisons between two unrelated ssRNA+ viruses are shown and reproducibility issues are assessed. Combined with the newest automatons and plant segmentation procedures, geometric morphometric tools could boost phenotypic features extraction and processing in an objective, reproducible manner.

plant biology↗

bioRxiv2017

Resolving ESCRT-III spirals at the intercellular bridge of dividing cells using 3D STORM imaging

The ESCRT machinery mediates membrane fission in a verity of processes in cells. According to the proposed mechanism, ESCRT-III proteins drive membrane fission by assembling into helical filaments on membranes. Yet, ESCRT-III filaments have never been directly visualized in a cellular process that utilizes this machinery for its function. Here we used 3D STORM imaging of endogenous ESCRT-III component IST1, to describe the structural organization of ESCRT-III during mammalian cytokinetic abscission. Using this approach, ESCRT-III ring and spiral assemblies were resolved at the intercellular tube of cells undergoing abscission. Characterization of these structures indicates the ESCRT-III helical filament undergoes remodeling during abscission. This work provides the first evidence that ESCRT-III proteins assemble into helical filaments in physiological context, indicating that the ESCRT-III machine indeed derives its contractile activity through spiral assemblies. Moreover, it provides new structural information on ESCRT-III filaments, which raise new mechanistic scenarios for ESCRT driven membrane constriction.

cell biology↗

bioRxiv2017

Impact of spatial organization on a novel auxotrophic interaction among soil microbes

A key prerequisite to achieve a deeper understanding of microbial communities and to engineer synthetic ones is to identify the individual metabolic interactions among key species and how these interactions are affected by different environmental factors. Deciphering the physiological basis of species-species and species-environment interactions in spatially organized environment requires reductionist approaches using ecologically and functionally relevant species. To this end, we focus here on a specific defined system to study the metabolic interactions in a spatial context among a plant-beneficial endophytic fungus Serendipita indica, and the soil-dwelling model bacterium Bacillus subtilis. Focusing on the growth dynamics of S. indica under defined conditions, we identified an auxotrophy in this organism for thiamine, which is a key co-factor for essential reactions in the central carbon metabolism. We found that S. indica growth is restored in thiamine-free media, when co-cultured with B. subtilis. The success of this auxotrophic interaction, however, was dependent on the spatial and temporal organization of the system; the beneficial impact of B. subtilis was only visible when its inoculation was separated from that of S. indica either in time or space. These findings describe a key auxotrophic interaction in the soil among organisms that are shown to be important for plant ecosystem functioning, and point to the potential importance of spatial and temporal organization for the success of auxotrophic interactions. These points can be particularly important for engineering of minimal functional synthetic communities as plant-seed treatments and for vertical farming under defined conditions.

systems biology↗

bioRxiv2017

Insights into cerebral haemodynamics and oxygenation utilising in vivo mural cell imaging and mathematical modelling

The neurovascular mechanisms underpinning the local regulation of cerebral blood flow (CBF) and oxygen transport remain elusive. In this study we have combined novel in vivo imaging of cortical microvascular and mural cell architecture with mathematical modelling of blood flow and oxygen transport, to provide new insights into CBF regulation that would be inaccessible in a conventional experimental context. Our study implicates vasomotion of smooth muscle actin-covered vessels, rather than pericyte-covered capillaries, as the main mechanism for modulating tissue oxygenation. We also resolve seemingly paradoxical observations in the literature around reduced blood velocity in response to arteriolar constrictions and deduce the cause to be propagation of constrictions to upstream penetrating arterioles. We provide support for pericytes acting as signalling conduits for upstream smooth muscle activation, and erythrocyte deformation as a complementary regulatory mechanism. Finally, we caution against the use of blood velocity as a proxy measurement for flow. Our combined imaging-modelling platform complements conventional experimentation allowing cerebrovascular physiology to be probed in unprecedented detail.

biophysics↗

bioRxiv2017

Development of an Intrinsic Skin Sensor for Blood Glucose Level with CRISPR-mediated Genome Editing in Epidermal Stem Cells

Biointegrated sensors can address various challenges in medicine by transmitting a wide variety of biological signals. A tempting possibility that has not been explored before is whether we can take advantage of genome editing technology to transform a small portion of endogenous tissue into an intrinsic and long-lasting sensor of physiological signals. The human skin and the epidermal stem cells have several unique advantages, making them particularly suitable for genetic engineering and applications in vivo. In this report, we took advantage of a novel platform for manipulation and transplantation of epidermal stem cells, and presented the key evidence that genome-edited skin stem cells can be exploited for continuous monitoring of blood glucose level in vivo. Additionally, by advanced design of genome editing, we developed an autologous skin graft that can sense glucose level and deliver therapeutic proteins for diabetes treatment. Our results revealed the clinical potential for skin somatic gene therapy.

cell biology↗

bioRxiv2017

Ecosystem functional response across precipitation extremes in a sagebrush steppe

BackgroundPrecipitation is predicted to become more variable in the western United States, meaning years of above and below average precipitation will become more common. Periods of extreme precipitation are major drivers of interannual variability in ecosystem functioning in water limited communities, but how ecosystems respond to these extremes over the long-term may shift with precipitation means and variances. Long-term changes in ecosystem functional response could reflect compensatory changes in species composition or species reaching physiological thresholds at extreme precipitation levels.\n\nMethodsWe conducted a five year precipitation manipulation experiment in a sagebrush steppe ecosystem in Idaho, United States. We used drought and irrigation treatments (approximately 50% decrease/increase) to investigate whether ecosystem functional response remains consistent under sustained high or low precipitation. We recorded data on aboveground net primary productivity (ANPP), species abundance, and soil moisture. We fit a generalized linear mixed effects model to determine if the relationship between ANPP and soil moisture differed among treatments. We used nonmetric multidimensional scaling to quantify community composition over the five years.\n\nResultsEcosystem functional response, defined as the relationship between soil moisture and ANPP, was similar among irrigation and control treatments, but the drought treatment had a greater slope than the control treatment. However, all estimates for the effect of soil moisture on ANPP overlapped zero, indicating the relationship is weak and uncertain regardless of treatment. There was also large spatial variation in ANPP within-years, which contributes to the uncertainty of the soil moisture effect. Plant community composition was remarkably stable over the course of the experiment and did not differ among treatments.\n\nDiscussionDespite some evidence that ecosystem functional response became more sensitive under sustained drought conditions, the response of ANPP to soil moisture was consistently weak and community composition was stable. The similarity of ecosystem functional responses across treatments was not related to compensatory shifts at the plant community level, but instead may reflect the insensitivity of the dominant species to soil moisture. These species may be successful precisely because they have evolved life history strategies which buffer them against precipitation variability.

ecology↗

bioRxiv2017

A novel dimeric active site and regulation mechanism revealed by the crystal structure of iPLA2β

Calcium-independent phospholipase A2{beta} (iPLA2{beta}) regulates several physiological processes including inflammation, calcium homeostasis and apoptosis. It is linked genetically to neurodegenerative disorders including Parkinsons disease. Despite its known enzymatic activity, the mechanisms underlying pathologic phenotypes remain unknown. Here, we present the first crystal structure of iPLA2{beta} that significantly revises existing mechanistic models. The catalytic domains form a tight dimer. The ankyrin repeat domains wrap around the catalytic domains in an outwardly flared orientation, poised to interact with membrane proteins. The closely integrated active sites are positioned for cooperative activation and internal transacylation. A single calmodulin binds and allosterically inhibits both catalytic domains. These unique structural features identify the molecular interactions that can regulate iPLA2{beta} activity and its cellular localization, which can be targeted to identify novel inhibitors for therapeutic purposes. The structure provides a well-defined framework to investigate the role of neurodegenerative mutations and the function of iPLA2{beta} in the brain.

biochemistry↗

bioRxiv2017

Rice paddy Nitrospirae encode and express genes related to sulfate respiration: proposal of the new genus Candidatus Sulfobium

Nitrospirae spp. distantly related to thermophilic, sulfate-reducing Thermodesulfovibrio species are regularly observed in environmental surveys of anoxic marine and freshwater habitats. However, little is known about their genetic make-up and physiology. Here, we present the draft genome of Nitrospirae bacterium Nbg-4 as a representative of this clade and analyzed its in situ protein expression under sulfate-enriched and sulfate-depleted conditions in rice paddy soil. The genome of Nbg-4 was assembled from replicated metagenomes of rice paddy soil that was used to grow rice plants in the presence and absence of gypsum (CaSO4x2H2O). Nbg-4 encoded the full pathway of dissimilatory sulfate reduction and showed expression thereof in gypsum-amended anoxic bulk soil as revealed by parallel metaproteomics. In addition, Nbg-4 encoded the full pathway of dissimilatory nitrate reduction to ammonia, which was expressed in bulk soil without gypsum amendment. The relative abundance of Nbg-4-related metagenome reads was similar under both treatments indicating that it maintained stable populations while shifting its energy metabolism. Further genome reconstruction revealed the potential to utilize butyrate, formate, H2, or acetate as electron donor, with the Wood-Ljungdahl pathway being expressed under both conditions. Comparison to publicly available Nitrospirae genome bins confirmed that the pathway for dissimilatory sulfate reduction is also present in related Nitrospirae recovered from groundwater. Subsequent phylogenomics showed that such microorganisms form a novel genus within the phylum Nitrospirae, with Nbg-4 as a representative species. Based on the widespread occurrence of this novel genus, we propose for Nbg-4 the name Candidatus Sulfobium mesophilum, gen. nov., spec. nov.\n\nImportanceRice paddies are indispensable for food supply but are a major source of the greenhouse gas methane. If not counterbalanced by cryptic sulfur cycling, methane emission from rice paddy fields would be even higher. However, the microorganisms involved in this sulfur cycling are little understood. By using an environmental systems biology approach of Italian rice paddy soil, we could retrieve the population genome of a novel member of the phylum Nitrospirae. This microorganism encoded the full pathway of dissimilatory sulfate reduction and expressed it in situ under sulfate-enriched and anoxic conditions. Phylogenomics and comparison to environmental surveys showed that such microorganisms are actually widespread in freshwater and marine environments. At the same time, they represent a yet undiscovered genus within the little explored Nitrospirae. Our results will be important to design enrichment strategies and postgenomic studies to fully understand the contribution of these novel Nitrospirae to the global sulfur cycle.

microbiology↗

bioRxiv2017

Timing of gene expression in a cell-fate decision system

During development, morphogens provide extracellular cues allowing cells to select a specific fate by inducing complex transcriptional programs. The mating pathway in budding yeast offers simplified settings to understand this process. Pheromone secreted by the mating partner triggers the activity of a MAPK pathway, which results in the expression of hundreds of genes. Using a dynamic expression reporter, we quantified the kinetics of gene expression in single cells upon exogenous pheromone stimulation and in the physiological context of mating. In both conditions, we observed striking differences in the timing of induction of mating-responsive promoters. Biochemical analyses and generation of synthetic promoter variants demonstrated how the interplay between transcription factor binding and nucleosomes contribute to determine the kinetics of transcription in a simplified cell-fate decision system.\n\nOne Sentence SummaryQuantitative and dynamic single cell measurements in the yeast mating pathway uncover a complex temporal orchestration of gene expression events.

systems biology↗

bioRxiv2018

Systematic analysis of mouse genome reveals distinct evolutionary and functional properties among circadian and ultradian genes

In living organisms, biological clocks regulate 24 h (circadian) molecular, physiological, and behavioral rhythms to maintain homeostasis and synchrony with predictable environmental changes. Harmonics of these circadian rhythms having periods of 8 hours and 12 hours (ultradian) have been documented in several species. In mouse liver, harmonics of the 24-hour period of gene transcription hallmarked genes oscillating with a frequency two or three times faster than the circadian circuitry. Many of these harmonic transcripts enriched pathways regulating responses to environmental stress and coinciding preferentially with subjective dawn and dusk. We hypothesized that these stress anticipatory genes would be more evolutionarily conserved than background circadian and non-circadian genes. To investigate this issue, we performed broad computational analyses of genes/proteins oscillating at different frequency ranges across several species and showed that ultradian genes/proteins, especially those oscillating with a 12-hour periodicity, are more likely to be of ancient origin and essential in mice. In summary, our results show that genes with ultradian transcriptional patterns are more likely to be phylogenetically conserved and associated with the primeval and inevitable dawn/dusk transitions.

bioinformatics↗