Biology subjects

Li, X.-Y.

Publications and source records attributed to Li, X.-Y..

18 recordsLinked to original sources

bioRxiv2026

Life finds a way: Integrative phylogenomics resolves an overlooked bivalve order with chromosome fusion and mitochondrial translational-code evolution

Resolving deep phylogenetic relationships requires integrating multiple lines of evidence, as distinct evolutionary forces shape signals from different genomic markers. Here, we investigate the systematics of the controversial APPD lineage (Anomiidae, Placunidae, Plicatulidae, and, by inference, Dimyidae) within Pectinida sensu lato using phylogenomic, comparative genomic, transcriptomic, proteomic, and morphological approaches. Our analyses consistently recover APPD as a monophyletic lineage sister to Limida and Pectinoidea, divergent at [~]428 Mya. With three novel high-quality genomes, extensive progressive chromosomal fusions demonstrate a reduction in chromosome number of the APPD lineage (6-13), compared with an ancestral 20 molluscan linkage groups (MLGs). Accompanied by extensive intrachromosomal gene-order scrambling, we identify one functional centromere in Placuna vitream flanked by two vestigial centromeric remnants on a single chromosome, providing a potential resource for investigating centromere inactivation and neocentromere formation. Mitochondrial genomes of APPD lineage exhibit unprecedented plasticity in translational decoding: Pododesmus employs the invertebrate mitochondrial code; Heteranomia employs +1 translational frameshifting to bypass in-frame TAG codons, whereas in Anomia, Enigmonia, Placuna, and Plicatulidae, TAA is reassigned to tyrosine and confirmed by proteomic evidence, which supports mitochondrial frameshifting in APPD lineage and defines a novel translation table for bivalves. Integrating phylogenetic distinctiveness, deep divergence, extreme karyotypic restructuring, unique mitochondrial features, and morphological diagnosability, we elevate the APPD lineage into Anomiida ord. nov. This revision resolves long-standing uncertainties for Pectinida sensu stricto and Limida, and establishes the APPD lineage as a valuable system for investigating chromosome fusion, centromere evolution, codon reassignment, and translational recoding. ClassificationBiological Sciences; Evolution SIGNIFICANCE STATEMENTWe have re-examined a controversial group of marine bivalves (Anomiidae, Placunidae, Plicatulidae, and Dimyidae). Our integrative approach shows that these animals split from scallops and their relatives more than 428 million years ago and have undergone drastic chromosomal fusions that reduced their chromosome number from 20 to as few as 6. Additionally, some species evolved unusual ways of reading their mitochondrial genetic code, either reassigning the stop codon to tyrosine or using +1 translational frameshifting to skip stop signals. The combination of deep evolutionary time and genomic divergence warrants recognizing them as a new order, Anomiida ord. nov. This work, as a case study, demonstrates how chromosome fusion and genetic code variation contribute to invertebrate diversity.

evolutionary biology↗

bioRxiv2025

Amoeboid-Mesenchymal Transition and the Proteolytic Control of Cancer Invasion Plasticity

Invasion plasticity allows malignant cells to toggle between collective, mesenchymal and amoeboid phenotypes while traversing extracellular matrix (ECM) barriers. Current dogma holds that collective and mesenchymal invasion programs trigger the mobilization of proteinases that digest structural barriers dominated by type I collagen, while amoeboid activity allows cancer cells to marshal mechanical forces to traverse tissues independently of ECM proteolysis. Here, we use cancer spheroid-3-dimensional matrix models, single-cell RNA sequencing, and human tissue explants to identify the mechanisms controlling mesenchymal versus amoeboid invasion. Unexpectedly, collective/mesenchymal- and amoeboid-type invasion programs - though distinct - are each characterized by active tunneling through ECM barriers, with expression of matrix-degradative metalloproteinases. CRISPR/Cas9-mediated targeting of a single membrane-anchored collagenase, MMP14/MT1-MMP, ablates tissue-invasive activity while co-regulating cancer cell transcriptional programs. Though changes in matrix architecture, nuclear rigidity, and metabolic stress as well as the presence of cancer-associated fibroblasts are proposed to support amoeboid activity, none of these changes restore invasive activity of MMP14-targeted cancer cells. While a requirement for MMP14 is bypassed in low-density collagen hydrogels, invasion by the proteinase-deleted cells is associated with nuclear envelope and DNA damage, highlighting a proteolytic requirement for maintaining nuclear integrity. Nevertheless, when cancer cells confront explants of live human breast tissue, MMP14 is again required to support invasive activity. Corroborating these results, spatial transcriptomic and immunohistological analyses of invasive human breast cancers identified clear expression of MMP14 in invasive cells that were further associated with degraded collagen, underlining the pathophysiologic importance of this proteinase in directing invasive activity in vivo.

cancer biology↗

bioRxiv2024

Neuregulin-1 Attenuates Myocardial Ischemia/Reperfusion Injury by Activating the UCP2/PINK1/LC3B-mediated Mitophagy

BACKGROUNDIschemia/reperfusion (I/R) injury may significantly affect the treatment outcomes and prognosis of patients with acute myocardial infarction following coronary artery recanalization. Available evidence suggests that neuregulin-1 (NRG-1) can provide a protection against myocardial I/R injury and is involved in various cardioprotective interventions by potential regulation of mitophagy. However, the molecular mechanisms linking NRG-1 and mitophagy remain to be clarified. This experiment aimed to determine whether NRG-1 postconditioning attenuated myocardial I/R injury through the regulation of mitophagy and to explore the underlying mechanisms. METHODBoth an in vivo myocardial I/R injury model of rats and an in vitro hypoxia/reoxygenation (H/R) model of H9C2 cardiomyocytes were applied. NRG-1 treatment was conducted immediately after I/R or H/R intervention. In the in vivo experiment, cardioprotective effects of NRG-1 were determined by infarct size, cardiac enzyme and histopathologic examinations. The potential downstream pathways and molecular targets of NRG-1 were screened by the RNA sequencing and the Protein-Protein Interaction Networks (PPI). The expression levels of mitochondrial uncoupling protein 2 (UCP2) and mitophagy-related protein in both the I/R myocardium and H/R cardiomyocytes were measured by immunofluorescence staining and Western blots. The activation of mitophagy was observed with the transmission electron microscopy (TEM) and JC-1 staining. RESULTSThe KEGG and GSEA analyses showed that the mitophagy-related pathways were enriched in the I/R myocardium treated with NRG-1, and UCP2 exhibited a significant correlation between mitophagy and interaction with PINK1. Meanwhile, the treatment with mitophagy inhibitor Mdivi-1 significant eliminated the cardioprotective effects of NRG-1 postconditioning in vivo, and the challenge with UCP2 inhibitor genipin could also attenuate the activating effect of NRG-1 postconditioning on mitophagy. Consistently, the in vitro experiment using H9C2 cardiomyocytes showd that NRG-1 treatment significantly up-regulated the expression levels of UCP2 and mitophagy-related proteins, and activated the mitophagy, whereas the challenge with small interfering RNA (siRNA)-mediated UCP2 knockdown abolished the effects of NRG-1. CONCLUSIONSNRG-1 postconditioning can produce a protection against the myocardial I/R injury by activating mitophagy through the UCP2/PINK1/LC3B signaling pathway.

molecular biology↗

bioRxiv2024

Intra-hypothalamic circuit orchestrates β-endorphin release following coital ejaculation in male mice

Survey-based evidence suggests that men experience a distinct post-ejaculation affective state1,2, marked by intense pleasure sometimes compared to the euphoric rush from intravenous injection of opioid drugs such as heroin3. However, the intrinsic neural circuit mechanisms underlying the ejaculation-triggered affective state remain unclear. Here, we discovered that Calbindin1-expressing (Calb1+) neurons in the preoptic area (POA) of the hypothalamus, an evolutionarily conserved regulatory region for male mating behavior4, are specifically activated during ejaculation in male mice. Inhibiting POA Calb1+ neurons prolongs mating and delays ejaculation. Importantly, POA Calb1+ neurons transmit the ejaculation signal and activate proopiomelanocortin-expressing (Pomc+) neurons in the arcuate nucleus of the hypothalamus, which show robust and sustained activity lasting for tens of seconds, specifically upon ejaculation. This activity is accompanied by elevated levels of {beta}-endorphins5, opioid peptides secreted by Pomc+ neurons, post-ejaculation in male mice. Optogenetic activation of Pomc+ neurons increases {beta}-endorphins levels and conditioned placed preference, similar to ejaculation. Conversely, intracerebroventricular (i.c.v.) infusion of drugs blocking Pomc neuropeptides signaling eliminates ejaculation-conditioned place preference. Collectively, these results elucidate an intra-hypothalamic circuit from POA Calb1+ neurons to arcuate Pomc+ neurons that coordinate {beta}-endorphin release with ejaculation, shedding light on the neurobiological basis of the post-ejaculation affective state.

neuroscience↗

bioRxiv2023

The Complexity of Functional Connectivity Profiles of the Subgenual Anterior Cingulate Cortex and Dorsal Lateral Prefrontal Cortex in Major Depressive Disorder: a DIRECT Consortium Study

BackgroundThe subgenual anterior cingulate cortex (sgACC) plays a central role in the pathophysiology of major depressive disorder (MDD), and its functional interactive profile with the left dorsal lateral prefrontal cortex (DLPFC) is associated with transcranial magnetic stimulation (TMS) treatment outcomes. Nevertheless, previous research on sgACC functional connectivity (FC) in MDD has yielded inconsistent results, partly due to small sample sizes and limited statistical power. Furthermore, calculating sgACC-FC to target TMS individually is challenging. MethodsLeveraging a large multi-site cross-sectional sample (1660 MDD patients vs. 1341 healthy controls) from Phase II of the Depression Imaging REsearch ConsorTium (DIRECT), we systematically delineated case-control difference maps of sgACC-FC. Then, we explored the potential impact of such group-level abnormality profiles on the TMS target localization and clinical efficacy. Next, we developed an MDD big data-guided individualized TMS targeting algorithm to integrate group-level statistical maps with individual-level brain activity to localize TMS targets individually. ResultsWe found an enhanced sgACC-DLPFC FC in MDD patients compared to healthy controls (HC). Such group differences altered the position of the sgACC anti-correlation peak in the left DLPFC. In two independent clinical samples, we showed that the magnitude of TMS targets case-control differences in sgACC FC was related to clinical improvement. The MDD big data-guided individualized TMS targeting algorithm may generate individualized TMS targets that are clinically superior to group-level targets. InterpretationWe reliably delineated MDD-related abnormalities of sgACC-FC profiles in a large, independently ascertained sample and demonstrated the potential impact of such case-control differences on FC-guided localization of TMS targets. FundingMinistry of Science and Technology of the Peoples Republic of China, National Natural Science Foundation of China, and Chinese Academy of Sciences

neuroscience↗

bioRxiv2022

Neural Representations of Self-Generated Thought during Think-aloud fMRI

Is the brain at rest during the so-called resting-state? Ongoing experiences in the resting-state vary in unobserved and uncontrolled ways across time, individuals, and populations. However, the role of self-generated thoughts in resting-state fMRI remains largely unexplored. In this study, we collected real-time self-generated thoughts during "resting-state" fMRI scans via the think-aloud method (i.e., think-aloud fMRI), which required participants to report whatever they were currently thinking. We first investigated brain activation patterns during a think-aloud condition and found that significantly activated brain areas included all brain regions required for speech. We then calculated the relationship between divergence in thought content and brain activation during think-aloud and found that divergence in thought content was associated with many brain regions. Finally, we explored the neural representation of self-generated thoughts by performing representational similarity analysis (RSA) at three neural scales: a voxel-wise whole-brain searchlight level; a region-level whole-brain analysis using the Schaefer 400-parcels; at the systems level using the Yeo seven-networks. We found that "resting-state" self-generated thoughts were distributed across a wide range of brain regions, involving all seven Yeo networks. This study highlights the value of considering ongoing experiences during resting-state fMRI, as well as providing preliminary methodological support for think-aloud fMRI.

neuroscience↗

bioRxiv2021

Single-cell RNA sequencing uncovers the excitatory/inhibitory synaptic unbalance in the retrosplenial cortex after peripheral nerve injury

Nerve injury in the somatosensory pathway may induce maladaptive changes at the transcriptional or protein level, contributing to the development and maintenance of neuropathic pain. In contrast to the retrosplenial cortex (RSC), which processes nociceptive information and exhibits structural and molecular changes after nerve injury, detailed transcriptional changes in the RSC are not yet known. Here we confirm the involvement of the RSC in regulating pain sensation and observe that the same peripheral stimulation activates more retrosplenial neurons after nerve injury; reducing the activities of CaMKII+ splenial cells relieves peripheral pain hypersensitivity after nerve injury. Using a single-cell RNA sequencing (scRNA-seq) approach, we identified cell-type-specific gene expression changes after nerve injury, and the gene set enrichment analysis results revealed suppressed ion homeostasis in CaMKII+ neurons. Furthermore, examination of the expression of genes encoding ligand-gated ion channels showed a decrease in Gabar1a but an increase in Gria1 in CaMKII+ neurons; consistently, we confirmed the unbalanced excitatory/inhibitory synaptic transmission by using the electrophysiological recording approach. Moreover, micro-infusion of 1-Naphthyl acetyl spermine in the RSC to reduce excitatory synaptic transmission alleviated peripheral pain hypersensitivity. Our data confirm the involvement of the RSC in pain regulation and provide information on cell type-dependent transcriptomic changes after nerve injury, which will contribute to the understanding of the mechanisms mediating neuropathic pain.

neuroscience↗

bioRxiv2021

Effects of cover crops on beetle assemblages in tea plantations

Beetles are visible members of food webs in tea plantations, with high species richness and abundance. Many tea pests, as well as natural enemies, are members of this order, so a knowledge of how groundcovers affect beetles can aid pest management. We collected beetles in a replicated field experiment in the Wuyi Mountains, Fujian Province China. Tea was intercropped with Paspalum notatum or Chamaecrista rotundifolia, or rows were cleared to bare ground, or in the control they were left unmanaged to allow weeds to grow naturally. Sampling, done by sweep netting and vegetation beating, was conducted monthly, between May 2006 and April 2008, and Coleoptera abundance, biomass, species richness and assemblage structures were compared between groundcover treatments. Total beetle abundance and species richness were significantly higher in tea intercropped with C. rotundifolia and bare ground than in naturally grown weedy control. Whilst there was no difference between predator assemblages among treatments for any measure, herbivores were more abundant, weighed more, and were more diverse in C. rotundifolia treatments than in weedy control. Biomass and species richness were also greater in plots with P. notatum groundcover than those in weedy control. We found that beetle assemblages varied both seasonally and with ground cover treatment, but the potential pest control impact of more species-rich beetle assemblages was mixed, and further work is needed to gain information on trophic groups with potential benefits for use in non-insecticidal pest management.

ecology↗

bioRxiv2021

Deconstruction of the retrosplenial granular cortex for social behavior in the mouse model of fragile X syndrome

Deficits in fragile X mental retardation 1 protein lead to fragile X syndrome (FXS) with mental retardation and social activity disorder. Until now, the neuronal circuits that mediate the social impairments of FXS were mostly unclear. Accidently, we found fewer c-fos expression in RSG of KO than WT mice after social behavior test. Inactivation of RSG neurons decreased social novelty but not the sociability of naive mice. Interestingly, although the RSG neurons of KO mice had higher background activity, fewer social contact-related Ca2+ neurons were observed during social interaction test via one-photon Ca2+ imaging in freely-behaving mice. Strikingly, enhancing the activity of RSG neurons rescued the abnormal social novelty in KO mice. Further studies proved that the innervations from the subiculum and ACC to RSG contributes to the social behavior. Take together, we found that abnormal activity in the retrosplenial granular cortex (RSG) led to social novelty deficits in Fmr1-knockout (KO) mice. Moreover, selective manipulation of RSG neurons may be an effective strategy to treat the social deficits in FXS. One Sentence SummaryDeletion of FMRP leads to lower social-related neuronal activity in the RSG; this causes social novelty deficits in Fmr1-KO mice.

neuroscience↗

bioRxiv2020

The search for sexually antagonistic genes: Practical insights from studies of local adaptation and statistical genomics

Sexually antagonistic (SA) genetic variation--in which genotypes favoured in one sex are disfavoured in the other--is predicted to be common and has been documented in several animal and plant populations, yet we currently know little about its pervasiveness among species or its population genetic basis. Recent applications of genomics in studies of SA genetic variation have highlighted considerable methodological challenges to the identification and characterisation of SA genes, raising questions about the feasibility of genomic approaches for inferring SA selection. The related fields of local adaptation and statistical genomics have previously dealt with similar challenges, and lessons from these disciplines can therefore help overcome current difficulties in applying genomics to study SA genetic variation. Here, we integrate theoretical and analytical concepts from local adaptation and statistical genomics research--including FST and FIS statistics, genome-wide association studies (GWAS), pedigree analyses, reciprocal transplant studies, and evolve-and-resequence (E&R) experiments--to evaluate methods for identifying SA genes and genome-wide signals of SA genetic variation. We begin by developing theoretical models for between-sex FST and FIS, including explicit null distributions for each statistic, and using them to critically evaluate putative signals of sex-specific selection in previously published datasets. We then highlight new statistics that address some of the limitations of FST and FIS, along with applications of more direct approaches for characterising SA genetic variation, which incorporate explicit fitness measurements. We finish by presenting practical guidelines for the validation and evolutionary analysis of candidate SA genes and discussing promising empirical systems for future work. Impact SummaryGenome sequences carry a record of the evolutionary and demographic histories of natural populations. Research over the last two decades has dramatically improved our ability to detect genomic signals of adaptation by natural selection, including several widely-used methods for identifying genes underlying local adaptation and quantitative trait variation. Yet the application of these methods to identify sexually antagonistic (SA) genes--wherein variants that are adaptive for one sex are maladaptive for the other--remains under-explored, despite the potential importance of SA selection as a mechanism for maintaining genetic variation. Indeed, several lines of evidence suggest that SA genetic variation is common within animal and plant populations, underscoring the need for analytical methods that can reliably identify SA genes and genomic signals of SA genetic variation. Here, we integrate statistics and experimental designs that were originally developed within the fields of local adaptation and statistical genomics and apply them to the context of sex-specific adaptation and SA genetic variation. First, we evaluate and extend statistical methods for identifying signals of SA variation from genome sequence data alone. We then apply these methods to re-analyse previously published datasets on allele frequency differences between sexes--a putative signal of SA selection. Second, we highlight more direct approaches for identifying SA genetic variation, which utilise experimental evolution and statistical associations between individual genetic variants and fitness. Third, we provide guidelines for the biological validation, evolutionary analysis, and interpretation of candidate SA polymorphisms. By building upon the strong methodological foundations of local adaptation and statistical genomics research, we provide a roadmap for rigorous analyses of genetic data in the context of sex-specific adaptation, thereby facilitating insights into the role and pervasiveness of SA variation in adaptive evolution.

evolutionary biology↗

bioRxiv2019

CsHscB as a novel TLR2 agonist from carcinogenic liver fluke Clonorchis sinensis modulates host immune response

Clonorchis sinensis-a fluke dwelling on the intrahepatic bile ducts causes clonorchiasis. During C. sinensis infection, worm-host interaction results in activation of PRRs and further triggers immune responses which determine the outcome of infection. However, the mechanisms by which pathogen-associated molecules patterns from C. sinensis interacted with TLRs were poorly understood. In the present study, we identified a [~]34 kDa lipoprotein CsHscB from C. sinensis which physically bound with TLR2. We also found that recombinant CsHscB (rCsHscB) potently activated macrophage to express various proteins including TLR2, CD80, MHCII, and cytokines like IL-6, TNF-, and IL-10 in a TLR2-dependent manner but rCsHscB failed to induce IL-10 in macrophages from Tlr2-/- mice. Moreover, ERK1/2 activation was required for rCsHscB-induced IL-10 production in macrophages. In vivo study revealed that rCsHscB triggered a high induction of IL-10 in the wild-type (WT) but not in Tlr2-/- mice. Our data thus demonstrate that rCsHscB from C. sinensis is an unidentified TLR2 agonist with immune regulatory activities, and may have some therapeutic implications in future beyond parasitology.

immunology↗

bioRxiv2019

Chromatin 3D structure reconstruction with consideration of adjacency relationship among genomic loci

Chromatin 3D conformation plays important roles in regulating gene or protein functions. High-throughout chromosome conformation capture (3C)-based technologies, such as Hi-C, have been exploited to acquire the contact frequencies among genomic loci at genome-scale. Various computational tools have been proposed to recover the underlying chromatin 3D structures from in situ Hi-C contact map data. As connected residuals in a polymer, neighboring genomic loci have intrinsic mutual dependencies in building a 3D conformation. However, current methods seldom take this feature into account. We present a method called ShNeigh, which combines the classical MDS technique with local dependence of neighboring loci modelled by a Gaussian formula, to infer the best 3D structure from noisy and incomplete contact frequency matrices. The results obtained on simulations and real Hi-C data showed, while keeping the high-speed nature of classical MDS, ShNeigh is more accurate and robust than existing methods, especially for sparse contact maps. A Matlab implementation of the proposed method is available at https://github.com/fangzhen-li/ShNeigh.\n\nAuthor summaryWe propose a new method to infer a consensus 3D genome structure from a Hi-C contact map. The novelty of our method is that it takes into accounts the adjacency of genomic loci along chromosomes. Specifically, the proposed method penalizes the optimization problem of the classical multidimensional scaling method with a smoothness constraint weighted by a function of the genomic distance between the pairs of genomic loci. We demonstrate this optimization problem can still be solved efficiently by a classical multidimensional scaling method. We then show that the method can recover stable structures in high noise settings. We also show that it can reconstruct similar structures from data obtained using different restriction enzymes.

bioinformatics↗

bioRxiv2018

Effects of the maternal factor Zelda on zygotic enhancer activity in the Drosophila embryo

The maternal factor Zelda is broadly bound to zygotic enhancers during early fly embryogenesis, and has been shown to be important for the expression of a large number of genes. However, its function remains poorly understood. Here, we carried out detailed analysis of the functional role of Zelda on the activities of a group of enhancers that drive patterned gene expression along the anterior -posterior axis. We found that among these enhancers, only one lost its activity entirely when all its Zelda bind sites were mutated. For all others, mutations of all of their Zelda binding sites only had limited effect, which varied temporally and spatially. These results suggest that Zld may exert a quantitative effect on a broad range of enhancers, which presumably is critical to generate highly diverse spatial and temporal expression patterns for different genes in the developmental gene network in fly embryo. Lastly, we found that the observed effect of Zelda site mutations was much stronger when a mutant enhancer was tested using a BAC based reporter construct than a simple reporter construct, suggesting that the effect of Zld is dependent on chromatin environment.

developmental biology↗

bioRxiv2018

Mutation of sequences flanking and separating transcription factor binding sites in a Drosophila enhancer significantly alter its output

Here we explore how mutating different sequences in an enhancer that regulates patterned gene expression in Drosophila melanogaster embryos can affect its output. We used quantitative imaging to analyze the effects of a wide variety of mutations in the hunchback distal anterior enhancer. This enhancer has been shown to respond to the anterior morphogen Bicoid, but we found that mutations in only one of the five strong Bicoid sites in the enhancer has a significant effect on its binding. The pioneer factor Zelda, which binds to this enhancer and is the only other factor implicated in its activity besides Bicoid. However, we found that mutations of all its sites only has modest effect that is limited to reduction of its output in more posterior regions of the embryo, where Bicoid levels are low. In contrast to the modest effects of mutating known transcription factor binding sites, randomizing the sequences between Zelda and Bicoid sites significantly compromised enhancer activity. Finer mapping suggested that the sequences that determine activity are broadly distributed in the enhancer. Mutations in short sequences flanking Bicoid binding sites have stronger effects than mutations to Bicoid sites themselves, highlighting the complex and counterintuitive nature of the relationship between enhancer sequence and activity.

developmental biology↗

bioRxiv2018

Zelda potentiates transcription factor binding to zygotic enhancers by increasing local chromatin accessibility during early Drosophila melanogaster embryogenesis.

The maternally deposited transcription factor Zelda binds to and is required for the activation of a large number of genes in early Drosophila development, and has been suggested to act as a pioneer factor. In this study, we investigated the temporal dynamics of Zelda binding along with the maternal patterning factors Dorsal and Caudal during early embryogenesis. We found in regions bound by Zelda and either Dorsal or Caudal, Zelda binding was detected, and reached maximum levels, earlier than Caudal and Dorsal, providing support of its role as a pioneer factor. We found that Dorsal and Caudal binding correlated strongly with Zelda binding at mitotic cycle 12, suggesting that Zelda is important for early binding by these factors and early onset of their target gene expression. At the same time, we show that among Dorsal target enhancers, the dorsal and ventral ectoderm enhancers are much more strongly associated with Zelda than mesoderm enhancers, revealing an additional function of Zelda in coordinating spatial activity of enhancers. We have also investigated the role of Zelda on chromatin structure. We found that in early embryos, before Dorsal and Caudal are bound at significant levels, Zelda binding is associated with histone acetylation and local histone depletion. These chromatin associated changes accompanied with increased local chromatin accessibility were also detected around Zelda peaks in coding sequences that do not appear to play a role in subsequent transcription factor binding. These findings suggest that Zelda binding itself can lead to chromatin structural changes. Finally, we found that Zelda motifs, both bound and unbound, tend to be associated with positioned nucleosomes, which we suggest may be important for the regulatory specificity of enhancers.

developmental biology↗

bioRxiv2017

Temperate phages as frequency-dependent weapons in bacterial competition

Microbial communities are accompanied by a diverse array of viruses. Through infections of abundant microbes, these viruses have the potential to mediate competition within the community, effectively weakening competitive interactions and promoting coexistence. This is of particular relevance for host-associated microbial communities, since the diversity of the microbiota has been linked to host health and functioning. Here, we study the interaction between two key members of the microbiota of the freshwater metazoan Hydra vulgaris. The two commensal bacteria Curvibacter sp. and Duganella sp. protect their host from fungal infections, but only if both of them are present. Coexistence of the two bacteria is thus beneficial for Hydra. Intriguingly, Duganella sp. appears to be the superior competitor in vitro due to its higher growth rate when both bacteria are grown seperately, but in coculture the outcome of competition depends on the relative initial abundances of the two species. The presence of an inducible prophage in the Curvibacter sp. genome which is able to lytically infect Duganella sp., led us to hypothesise that the phage modulates the interaction between these two key members of the Hydra microbiota. Using a mathematical model we show that the interplay of the lysogenic life-cycle of the Curvibacter phage and the lytic life-cycle on Duganella sp. can explain the observed complex competitive interaction between the two bacteria. Our results highlight the importance of taking lysogeny into account for understanding microbe-virus interactions and show the complex role phages can play in promoting coexistence of their bacterial hosts.

microbiology↗

bioRxiv2017

Dense Bicoid Hubs Accentuate Binding along the Morphogen Gradient

Morphogen gradients direct the spatial patterning of developing embryos, however, the mechanisms by which these gradients are interpreted remain elusive. Here we perform in vivo single molecule imaging in early Drosophila melanogaster embryos of the transcription factor Bicoid that forms a gradient and initiates patterning along the anteroposterior axis. We observe that Bicoid binds to DNA with a rapid off-rate, such that its average occupancy at target loci is on-rate dependent, a property required for concentration-sensitive regulation. Surprisingly, we also observe abundant specific DNA binding in posterior nuclei, where Bicoid levels are vanishingly low. Live embryo imaging reveals spatiotemporal \"hubs\" of local high Bicoid concentration that are dependent on the ubiquitous maternal factor Zelda. We propose that localized modulation of transcription factor on-rates via clustering, provides a general mechanism to facilitate binding to low-affinity targets, and that this may be a prevalent feature directing other developmental transcription networks.

developmental biology↗

bioRxiv2017

Sexual reproduction as bet-hedging

In evolutionary biology, bet-hedging refers to a strategy that reduces the variance of reproductive success at the cost of reduced mean reproductive success. In unpredictably fluctuating environments, bet-hedgers benefit from higher geometric mean fitness despite having lower arithmetic mean fitness than their specialist competitors. We examine the extent to which sexual reproduction can be considered a type of bet-hedging, by clarifying past arguments, examining parallels and differences to evolutionary games, and by presenting a simple model examining geometric and arithmetic mean payoffs of sexual and asexual reproduction. Sex typically has lower arithmetic mean fitness than asex, while the geometric mean fitness can be higher if sexually produced offspring are not identical. However, asexual individuals that are heterozygotes can gain conservative bet-hedging benefits of similar magnitude while avoiding the costs of sex. This highlights that bet-hedging always has to be specified relative to the payoff structure of relevant competitors. It also makes it unlikely that sex, at least when associated with significant male production, evolves solely based on bet-hedging in the context of frequently and repeatedly occupied environmental states. Future work could usefully consider bet-hedging in open-ended evolutionary scenarios with de novo mutations.

evolutionary biology↗