Biology subjects

Durand, S.

Publications and source records attributed to Durand, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

HEIP1 is required for efficient meiotic crossover implementation and is conserved from plants to humans

Crossovers (CO) shuffle genetic information and physically connect homologous chromosome pairs, ensuring their balanced segregation during meiosis. COs arising from the major class I pathway require the activity of a well-conserved ZMMs group of proteins which, in conjunction with MLH1, facilitate the maturation of DNA recombination intermediates specifically into COs. The HEIP1 protein was identified in rice and proposed to be a new, plant-specific member of the ZMM group. Here we establish and decipher the function of the Arabidopsis thaliana HEIP1 homolog in meiotic crossover formation and report its wide conservation in eukaryotes. We show that the loss of Arabidopsis HEIP1 elicits a marked reduction in meiotic COs and their redistribution towards chromosome ends. Epistasis analysis showed that AtHEIP1 acts specifically in the class I CO pathway. Further, we show that HEI1P acts both prior to crossover designation, as the number of MLH1 foci is reduced in heip1, and at the maturation step of MLH1-marked sites into COs. Despite the HEIP1 protein being predicted to be primarily unstructured and very divergent at the sequence level, we identified homologs of HEIP1 in an extensive range of eukaryotes, including mammals.

genetics↗

bioRxiv2022

Smurfness-based two-phase model of ageing helps deconvolve the ageing transcriptional signature

Ageing is characterised at the molecular level by six transcriptional hallmarks of ageing, that are commonly described as progressively affected as time passes. By contrast, the Smurf assay separates high-and-constant-mortality risk individuals from healthy, zero-mortality risk individuals, based on increased intestinal permeability. Performing whole body total RNA sequencing, we found that Smurfness distinguishes transcriptional changes associated with chronological age from those associated with biological age. We show that transcriptional heterogeneity increases with chronological age in non-Smurf individuals preceding the other five hallmarks of ageing, that are specifically associated with the Smurf state. Using this approach, we also devise targeted pro-longevity genetic interventions delaying entry in the Smurf state. We anticipate that increased attention to the evolutionary conserved Smurf phenotype will bring about significant advances in our understanding of the mechanisms of ageing. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=150 HEIGHT=200 SRC="FIGDIR/small/517330v5_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@37b39org.highwire.dtl.DTLVardef@8ef8f0org.highwire.dtl.DTLVardef@797299org.highwire.dtl.DTLVardef@1529b0d_HPS_FORMAT_FIGEXP M_FIG The two-phase model of ageing allows to study separately the effect of chronological and physiological age. (A) Classic approaches for studying ageing tend to consider it as a black box affecting all individuals progressively from birth to death. Instead, the Smurf phenotype shows that life can be divided into two consecutive phases separated by an abrupt transition. (B) All individuals undergo this transition at a different moment in their life, prior to death. This allows us to switch from population based approaches, comparing bulks of age-matched individuals through time, to individuals-centred approaches relying on direct access to their transition status. (C) Such paradigm shift shows that hallmarks of ageing long thought to progressively change with age are actually mostly affected in a growing proportion of Smurfs, allowing for the identification of the chain of events accompanying ageing and death from natural causes. (D) By studying the behaviour of the ageing transcriptome as a function of chronological age and Smurfness separately, we demonstrate that the progressively changing transcriptional ageing signature, as described in Frenk & Houseley (2018), is in fact the convolution changes accompanying chronological age signature (increased transcriptional noise) and changes associated with Smurfness (or biological age) signature (increased stress response and inflammation, decreased expression of ribosomal and mitochondrial genes). We also identified a hallmark partially associated with only old Smurfs (ATH5), suggesting that chronological age can affect, late in life, the Smurf response. C_FIG

systems biology↗

bioRxiv2022

Distribution of sex ratio distorters in natural populations of the isopod Armadillidium vulgare

In the isopod Armadillidium vulgare, many females produce progenies with female-biased sex ratios, due to two feminizing sex ratio distorters (SRD): Wolbachia endosymbionts and the f element. We investigated the distribution and population dynamics of these SRD and mitochondrial DNA variation in 16 populations from Europe and Japan. Confirming and extending results from the 1990s, we found that the SRD are present at variable frequencies in populations, and that the f element is overall more frequent than Wolbachia. The two SRD never co-occur at high frequency in any population, suggesting an apparent mutual exclusion. We also detected Wolbachia or the f element in some males, which likely reflects insufficient titer to induce feminization or presence of masculinizing alleles. Our results are consistent with a single integration event of a Wolbachia genome in the A. vulgare genome at the origin of the f element, which contradicts an earlier hypothesis of frequent losses and gains. We identified strong linkage between Wolbachia strains and mitochondrial haplotypes, but no association between the f element and mitochondrial background. Our results open new perspectives on SRD evolutionary dynamics in A. vulgare, the evolution of genetic conflicts and their impact on the variability of sex determination systems.

evolutionary biology↗

bioRxiv2022

Dual control of meiotic crossover patterning

Most meiotic crossovers (COs), called class I crossovers, are produced by a conserved pathway catalyzed by the ZMM proteins; COs are limited in number, typically to 1-3 per chromosome, and are prevented from occurring close to one other by crossover interference1-3. In many species, CO number is subject to dimorphism between males and females, and a lower CO number is associated with shorter chromosome axes and stronger interference4. How the patterning of COs is imposed, however, remains poorly understood. Here, we show that overexpression of the ZMM protein HEI10 increases COs and reduces crossover interference but maintains sexual dimorphism; shorter axes length in female meiosis is still associated with fewer COs and stronger interference than in male meiocytes. Disrupting the synaptonemal complex (SC) by mutating ZYP1 also leads to an increase in class I COs but, in contrast, abolishes interference and disrupts the link between chromosome axis length and COs, with female and male meiocytes having the same CO frequency despite different axis lengths. Combining HEI10 overexpression and zyp1 mutation leads to a massive increase in class I COs and absence of interference, while axes lengths are still unaffected. These observations support, and can be effectively predicted by, a recently proposed coarsening model5,6 in which HEI10 diffusion is funneled by the central element of the SC before coarsening into large, well-spaced CO-promoting droplets. Given the conservation of the components, this model may account for CO patterning in many eukaryotes.

genetics↗

bioRxiv2022

Discovery of a druggable copper-signaling pathway that drives cell plasticity and inflammation

Inflammation is a complex physiological process triggered in response to harmful stimuli. It involves specialized cells of the immune system able to clear sources of cell injury and damaged tissues to promote repair. Excessive inflammation can occur as a result of infections and is a hallmark of several diseases. The molecular basis underlying inflammatory responses are not fully understood. Here, we show that the cell surface marker CD44, which characterizes activated immune cells, acts as a metal transporter that promotes copper uptake. We identified a chemically reactive pool of copper(II) in mitochondria of inflammatory macrophages that catalyzes NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with a rationally-designed dimer of metformin triggers distinct metabolic and epigenetic states that oppose macrophage activation. This drug reduces inflammation in mouse models of bacterial and viral (SARS-CoV-2) infections, improves well-being and increases survival. Identifying mechanisms that regulate the plasticity of immune cells provides the means to develop next-generation medicine. Our work illuminates the central role of copper as a regulator of cell plasticity and unveils a new therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

cell biology↗

bioRxiv2022

Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

The expression of the pluripotency factors OCT4, SOX2, KLF4 and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, cycles of brief OSKM expression do not change cell identity but can reverse markers of aging in cells and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic and metabolomic changes towards a younger configuration in multiple tissues and in the serum.

cell biology↗

bioRxiv2022

Limb Specific Failure of Proliferation and Translation in the Mesenchyme Leads to Skeletal Defects in Diamond Blackfan Anemia

AbstractRibosomopathies are a class of disorders caused by defects in the structure or function of the ribosome and characterized by tissue-specific abnormalities. Diamond Blackfan anemia (DBA) arises from different mutations, predominantly in genes encoding ribosomal proteins (RPs). Apart from the anemia, skeletal defects are among the most common anomalies observed in patients with DBA, but they are virtually restricted to radial ray and other upper limb defects. What leads to these site-specific skeletal defects in DBA remains a mystery. Using a novel mouse model for RP haploinsufficiency, we observed specific, differential defects of the limbs. Using complementary in vitro and in vivo approaches, we demonstrate that reduced WNT signaling and subsequent increased {beta}-catenin degradation in concert with increased expression of p53 contribute to mesenchymal lineage failure. We observed differential defects in the proliferation and differentiation of mesenchymal stem cells (MSCs) from the forelimb versus the hind limbs of the RP haploinsufficient mice that persisted after birth and were partially rescued by allelic reduction of Trp53. These defects are associated with a global decrease in protein translation in RP haploinsufficient MSCs, with the effect more pronounced in cells isolated from the forelimbs. Together these results demonstrate translational differences inherent to the MSC, explaining the site-specific skeletal defects observed in DBA.

cell biology↗

bioRxiv2021

Induction of transposable element expression is central to innate sensing

Evidence indicates that transposable elements (TEs) stimulate innate sensing pathways in various pathologies but it is not clear whether they are sensed during normal physiological responses. Here we show that, during activation with an exogenous pathogen associated molecular pattern (PAMP), dendritic cells (DCs) epigenetically remodel heterochromatin at TEs by depleting the methyltransferase Suv39h1 and reducing histone-3 lysine-9 trimethylation (H3K9me3). TLR4 signaling activates TE expression to enhance innate responses through the DNA sensor cGAS. Cytosolic cGAS-bound DNA comprised LINE1 TEs as the predominant endogenous ligands. Concordantly, LINE1 inhibition attenuated the type-I IFN response to LPS and rescued influenza virus infection. We propose that in healthy cells, exogenous PAMPs epigenetically activate self-derived PAMPs (LINE1) that engage cGAS to enhance responses. These data explain why pathogens employ redundant and broad innate immune countermeasures, to suppress activation of host PAMPs and illustrate a hitherto unappreciated role for host genome-derived PAMPs in response to pathogens.

immunology↗

bioRxiv2021

APOK3, a pollen killer antidote in Arabidopsis thaliana

According to the principles of heredity, each parental allele of hybrids equally participates in the progeny. At some loci, however, it happens that one allele is favored to the expense of the other. Gamete killers are genetic systems where one allele (the killer) triggers the death of the gametes carrying the other (killed) allele. They have been found in many organisms, and are of major interest to understand mechanisms of evolution and speciation. Gamete killers are particularly prevalent in plants, where they can compromise crop breeding. Here, we deciphered a pollen killer in Arabidopsis thaliana by exploiting natural variation, de novo genomic sequencing and mutants, and analyzing segregations in crosses. We found that the killer allele carries an antidote gene flanked by two elements mandatory for the killing activity. We identified the gene encoding the antidote, a chimeric protein addressed to mitochondria. This gene appeared in the species by association of domains recruited from other genes, and it recently underwent duplications within a highly variable locus, particularly in the killer genotypes. Exploring the species diversity, we identified sequence polymorphisms correlated with the antidote activity.

genetics↗

bioRxiv2021

Radiotherapy induces specific miRNA expression profiles in glioblastoma exosomes

BackgroundGlioblastoma (GBM) is the most aggressive and frequent primary brain tumor during adulthood. One of the major treatments is the association of surgery and a combination of chemo and radiotherapies. Despite its immediate efficiency, it fails to prevent the cancer recurrence in the irradiated area due to radioresistance mechanisms. MicroRNAs (miRNAs or miR) are small non-coding, single strand RNA molecules encoding to various specific genes and able to regulate their expression and induce the tumor cell survival leading to radioresistance. Small extracellular vesicles (EVs), or exosomes released by tumor cells in tumor microenvironment and blood circulation are able to transport and diffuse miRNAs and affect the microenvironment by spreading the miRNAs, which drive radioresistance. AimsO_LITo identify the variations of miRNAs expression induced by irradiation in human glioblastoma U87-MG cells and their secreted exosomes collected in supernatants. C_LIO_LITo analyze the miRNAs variations in EVs-derived from the plasma of patients during radiotherapy, in order to identify a miRNA signature induced by radiotherapy in a liquid biopsy. C_LI Materiel and methodsU87-MG cells were cultured on plates and exposed to irradiation. miRNAs analyzes were performed in cells and in EVs isolated from cell supernatants to determine miRNAs expressions both in cells and in secreted exosomes before and after irradiation. Plasma-derived EVs were collected from 4 glioblastoma patients before and after surgery and radiotherapy treatments. ConclusionThe analysis of miRNAs expression profiles in both GBM cells and their derived EVs revealed that miR profile changes after irradiation. However, the number of similar miR between cells or EVs, following cell irradiation, was restricted to 3 miRs alone suggesting that the irradiation-induced changes in the miR profile in the cells and their EVs are not closely linked. In this context, the miR profile in EVs from patients plasma was investigated to establish a potential link with the miRNAs profile observed in EVs from irradiated cells and to assess its relationship with the response to radiotherapy. Three miRs (different from those identified in cells) were common between EVs derived from cells and patients derived-exosomes. These miRs detected in circulating EVs could provide a specific and reliable signature in response to ionizing radiation, which could be useful for monitoring the effectiveness of radiotherapy. Further experiments on a larger patients population with clinical data could also help to define whether this signature might have a prognostic value on the response to radiotherapy.

cancer biology↗

bioRxiv2021

Interplay between intrinsic reprogramming potential and microenvironment controls neuroblastoma cell plasticity and identity

Two cell identities, noradrenergic and mesenchymal, have been characterized in neuroblastoma cell lines according to their epigenetic landscapes relying on specific circuitries of transcription factors. Yet, their relationship and relative contribution in patient tumors remain poorly defined. Here, we demonstrate that the knock-out of GATA3, but not of PHOX2A or PHOX2B, in noradrenergic cells induces a mesenchymal phenotype. Our results document spontaneous plasticity in several models between both identities and show that plasticity relies on epigenetic reprogramming. We demonstrate that an in vivo microenvironment provides a powerful pressure towards a noradrenergic identity for these models. Consistently, tumor cells with a mesenchymal identity are not detected in a series of PDX models. Further study of the intra-tumor noradrenergic heterogeneity reveals two distinct cell populations exhibiting features of chromaffin-like or sympathoblast-like cells. This work emphasizes that both external cues of the environment and intrinsic factors control plasticity and cell identity in neuroblastoma.

cancer biology↗

bioRxiv2020

Multi-area functional modules mediate feedforward and recurrent processing in visual cortical hierarchy

The visual cortex is organized hierarchically, but the presence of extensive recurrent and parallel pathways make it challenging to decipher how signals flow between neuronal populations. Here, we tracked the flow of spiking activity recorded from six interconnected levels of the mouse visual hierarchy. By analyzing leading and lagging spike-timing relationships among pairs of simultaneously recorded neurons, we created a cellular-scale directed network graph. Using a module-detection algorithm to cluster neurons based on shared connectivity patterns, we uncovered two multi-regional communication modules distributed across the hierarchy. The direction of signal flow between and within these modules, differences in layer and area distributions, and distinct temporal dynamics suggest that one module is positioned to transmit feedforward sensory signals, whereas the other integrates inputs for recurrent processing. These results suggest that multi-regional functional modules may be a fundamental feature of organization beyond cortical areas that supports signal propagation across hierarchical recurrent networks.

neuroscience↗

bioRxiv2020

Reconciling functional differences in populations of neurons recorded with two-photon imaging and electrophysiology

Extracellular electrophysiology and two-photon calcium imaging are widely used methods for measuring physiological activity with single-cell resolution across large populations of neurons in the brain. While these two modalities have distinct advantages and disadvantages, neither provides complete, unbiased information about the underlying neural population. Here, we compare evoked responses in visual cortex recorded in awake mice under highly standardized conditions using either imaging or electrophysiology. Across all stimulus conditions tested, we observe a larger fraction of responsive neurons in electrophysiology and higher stimulus selectivity in calcium imaging. This work explores which data transformations are most useful for explaining these modality-specific discrepancies. We show that the higher selectivity in imaging can be partially reconciled by applying a spikes-to-calcium forward model to the electrophysiology data. However, the forward model could not reconcile differences in responsiveness without sub-selecting neurons based on event rate or level of signal contamination. This suggests that differences in responsiveness more likely reflect neuronal sampling bias or cluster-merging artifacts during spike sorting of electrophysiological recordings, rather than flaws in event detection from fluorescence time series. This work establishes the dominant impacts of the two modalities respective biases on a set of functional metrics that are fundamental for characterizing sensory-evoked responses.

neuroscience↗

bioRxiv2019

Transformation of population code from dLGN to V1 facilitates linear decoding

How neural populations represent sensory information, and how that representation is transformed from one brain area to another, are fundamental questions of neuroscience. The dorsolateral geniculate nucleus (dLGN) and primary visual cortex (V1) represent two distinct stages of early visual processing. Classic sparse coding theories propose that V1 neurons represent local features of images. More recent theories have argued that the visual pathway transforms visual representations to become increasingly linearly separable. To test these ideas, we simultaneously recorded the spiking activity of mouse dLGN and V1 in vivo. We find strong evidence for both sparse coding and linear separability theories. Surprisingly, the correlations between neurons in V1 (but not dLGN) were shaped as to be irrelevant for stimulus decoding, a feature which we show enables linear separability. Therefore, our results suggest that the dLGN-V1 transformation reshapes correlated variability in a manner that facilitates linear decoding while producing a sparse code.

neuroscience↗

bioRxiv2019

Widespread presence of direction-reversing neurons in the mouse visual system

Direction selectivity - the preference of motion in one direction over the opposite - is a fundamental property of visual neurons across species. We find that a substantial proportion of direction selective neurons in the mouse visual system reverse their preferred direction of motion in response to drifting gratings at different spatiotemporal parameters. A spatiotemporally asymmetric filter model recapitulates our experimental observations.

neuroscience↗

bioRxiv2019

Novel regulation from novel interactions: Identification of an RNA sponge that controls the levels, processing and efficacy of the RoxS riboregulator of central metabolism in Bacillus subtilis

Small RNAs (sRNAs) are a taxonomically-restricted but transcriptomically-abundant class of post-transcriptional regulators. While potentially of importance, we know the function of few. This is in no small part because we lack global-scale methodology enabling target identification, this being especially acute in species without known RNA meeting point proteins (e.g. Hfq). We apply a combination of psoralen RNA cross-linking and Illumina-sequencing to identify RNA-RNA interacting pairs in vivo in Bacillus subtilis, resolving previously well-described interactants. Although sRNA-sRNA pairings are rare (compared with sRNA/mRNA), we identify a robust example involving the unusually conserved sRNA (RoxS/RsaE) and an unstudied sRNA that we term Regulator of small RNA A (RosA). This interaction is found in independent samples across multiple conditions. Given the possibility of a novel associated regulatory mechanism, and the rarity of well-characterised bacterial sRNA-sRNA interactions, we mechanistically dissect RosA and its interactants. RosA we show to be a sponge RNA, the first to be described in a Gram-positive bacterium. RosA interacts with at least two sRNAs, RoxS and FsrA. Unexpectedly, it acts differently on each. As expected of a sponge RNA, FsrA is sequestered by RosA. The RosA/RoxS interaction is more complex affecting not only the level of RoxS but also its processing and efficacy. Importantly, RosA provides the condition-dependent intermediary between CcpA, the key regulator of carbon metabolism, and RoxS. This not only provides evidence for a novel, and functionally important, regulatory mechanism, but in addition, provides the missing link between transcriptional and post-transcriptional regulation of central metabolism.

microbiology↗

bioRxiv2019

A survey of spiking activity reveals a functional hierarchy of mouse corticothalamic visual areas

The mammalian visual system, from retina to neocortex, has been extensively studied at both anatomical and functional levels. Anatomy indicates the cortico-thalamic system is hierarchical, but characterization of cellular-level functional interactions across multiple levels of this hierarchy is lacking, partially due to the challenge of simultaneously recording activity across numerous regions. Here, we describe a large, open dataset (part of the Allen Brain Observatory) that surveys spiking from units in six cortical and two thalamic regions responding to a battery of visual stimuli. Using spike cross-correlation analysis, we find that inter-area functional connectivity mirrors the anatomical hierarchy from the Allen Mouse Brain Connectivity Atlas. Classical functional measures of hierarchy, including visual response latency, receptive field size, phase-locking to a drifting grating stimulus, and autocorrelation timescale are all correlated with the anatomical hierarchy. Moreover, recordings during a visual task support the behavioral relevance of hierarchical processing. Overall, this dataset and the hierarchy we describe provide a foundation for understanding coding and dynamics in the mouse cortico-thalamic visual system.

neuroscience↗

bioRxiv2019

WiPP: Workflow for improved Peak Picking for Gas Chromatography-Mass Spectrometry (GC-MS) data

Lack of reliable peak detection impedes automated analysis of large scale GC-MS metabolomics datasets. Performance and outcome of individual peak-picking algorithms can differ widely depending on both algorithmic approach and parameters as well as data acquisition method. Comparing and contrasting between algorithms is thus difficult. Here we present a workflow for improved peak picking (WiPP), a parameter optimising, multi-algorithm peak detection for GC-MS metabolomics. WiPP evaluates the quality of detected peaks using a machine learning-based classification scheme based on seven peak classes. The quality information returned by the classifier for each individual peak is merged with results from different peak detection algorithms to create one final high quality peak set for immediate down stream analysis. Medium and low quality peaks are kept for further inspection. By applying WiPP to standard compound mixes and a complex biological dataset we demonstrate that peak detection is improved through the novel way to assign peak quality, an automated parameter optimisation, and results integration across different embedded peak picking algorithms. Furthermore, our approach can provide an impartial performance comparison of different peak picking algorithms. WiPP is freely available on GitHub (https://github.com/bihealth/WiPP) under MIT licence.

bioinformatics↗