Biology subjects

Chevalier, C.

Publications and source records attributed to Chevalier, C..

29 records · Page 2Linked to original sources

bioRxiv2022

Various tomato cultivars display contrasted morphological and molecular responses to a heat wave.

Climate change is one of the biggest threats that human society currently needs to face. Heat waves associated with global warming negatively affect plant growth and development and will increase in frequency. Tomato is one of the most produced and consumed fruit in the world but remarkable yield losses occur every year due to the sensitivity of many cultivars to heat stress. New insights into how tomato plants are responding to heat waves will contribute to the development of new cultivars with high yields under harsh temperature conditions. In this study, the analysis of microsporogenesis and pollen germination rate of eleven tomato cultivars after exposure to a simulated heat wave revealed differences between genotypes. The transcriptome of floral buds at two developmental stages of five cultivars selected based on their pollen germination tolerance or sensitivity, revealed common and specific molecular responses implemented by tomato cultivars to cope with heat waves. These data provide valuable insights into the underlying molecular adaptation of floral buds to heat stress and will contribute to the development of future climate resilient tomato varieties.

plant biology↗

bioRxiv2022

Ts66Yah, a refined Ts65Dn DS mouse model, unravels genetic interaction between regions homologous to Human chromosome 21 and the Scaf8-Pde10a genetic interval.

Down syndrome is caused by trisomy of human chromosome 21 (Hsa21). The understanding of phenotype-genotype relationships, the identification of driver genes and various proof-of-concepts for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to the human DS features. It carries an additional minichromosome with the Mir155 to Zbtb21 region of mouse chromosome 16 (Mmu16), homologous to Hsa21, encompassing around 90 genes, fused to the centromeric part of mouse chromosome 17 (Mmu17) fromPisd-ps2/Scaf8 to Pde10a, containing 46 genes, not related to Hsa21. Here, we report the investigation of a new model, Ts66Yah, generated by CrispR/Cas9 without the genomic region unrelated to Hsa21 on the minichromosome. As expected, Ts66Yah replicated DS cognitive features. However, certain phenotypes related to increased activity, spatial learning and molecular signatures, were changed suggesting genetic interactions between the Mir155-Zbtb21 and the Scaf8-Pde10a interval. Thus, Ts66Yah mice have a stronger construct and face validity for mimicking consequences of DS genetic overdosage. Furthermore, this report is the first to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to Hsa21.

genetics↗

bioRxiv2022

Pneumococcus triggers NFkB degradation in COMMD2 aggresome-like bodies.

NF-{kappa}B driven cellular immunity is essential for both pro- and anti-inflammatory responses to microbes, which makes it one of the most frequently targeted pathways by bacteria during pathogenesis. How NF-{kappa}B tunes the epithelial response to Streptococcus pneumoniae across the spectrum of commensal to pathogenic outcomes is not fully understood. In this study, we compare a commensal-like 6B ST90 strain to an invasive TIGR4 isolate and demonstrate, through comparative mass spectrometry of the p65 interactome, TIGR4 challenge triggers a novel interaction of COMMD2 with p65 and p62. Mechanistically, we show this complex mediates export of p65 for degradation and COMMD2 is necessary for altering host cellular immunity. With these results, we reveal for the first time a new bacterial pathogenesis mechanism to repress host inflammatory response though COMMD2 and p65 degradation while presenting a paradigm for diverging NF-{kappa}B responses to pneumococcus.

microbiology↗

bioRxiv2020

Cold Exposure Protects from Neuroinflammation Through Immunologic Reprogramming

Autoimmunity is energetically costly, but the impact of a metabolically active state on immunity and immune-mediated diseases is unclear. Ly6Chi monocytes are key effectors in CNS autoimmunity with elusive role in priming naive autoreactive T cells. Here we provide unbiased analysis of the immune changes in various compartments during cold exposure, and show that this energetically costly stimulus markedly ameliorates active experimental autoimmune encephalomyelitis (EAE). Cold exposure decreases MHCII on monocytes at steady-state and in various inflammatory mouse models, and suppresses T cell priming and pathogenicity through the modulation of monocytes. Genetic, or antibody-mediated monocyte depletion, or adoptive transfer of Th1- or Th17-polarized cells for EAE abolish the cold-induced effects on T cells or EAE, respectively. These findings provide a mechanistic link between environmental temperature and neuroinflammation, and suggest competition between cold-induced metabolic adaptations and autoimmunity as energetic trade-off beneficial for the immune-mediated diseases.

immunology↗

bioRxiv2020

Targeting the RHOA pathway improves learning and memory in Kctd13 and 16p11.2 deletion mouse models.

Gene copy number variants (CNV) have an important role in the appearance of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in the 16p11.2 deletion through the regulation of the RHOA pathway. Here, we target the pathway and rescue the cognitive phenotypes of the 16p11.2 deletion mouse models. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase (ROCK), in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 region. We focused our attention on the most robust cognitive phenotypes seen in the 16p11.2 models and we showed that a chronic fasudil treatment can restore object recognition memory in both mouse models but does not change other behavioural traits. These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the pertinence of the RHOA pathway as a therapeutic path and reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 CNV models. HIGHLIGHTS- Kctd13 haploinsufficiency recapitulates most of the behaviour phenotypes found in the 16p11.2 Del/+ models - Fasudil treatment restores Kctd13 and 16p11.2 Del/+ mutant phenotypes in novel location and novel object recognition memory tests - Fasudil treatment restores the RhoA pathway in Kctd13+/- and 16p11.2 Del/+ models

animal behavior and cognition↗

bioRxiv2020

Converting networks to predictive logic models from perturbation signalling data with CellNOpt

MotivationThe molecular changes induced by perturbations such as drugs and ligands are highly informative of the intracellular wiring. Our capacity to generate large data-sets is increasing steadily as new experimental approaches are developed. A useful way to extract mechanistic insight from the data is by integrating them with a prior knowledge network of signalling to obtain dynamic models. Logic models scale better with network size than alternative kinetic models, while keeping the interpretation of the model simple, making them particularly suitable for large datasets. ResultsCellNOpt is a collection of Bioconductor R packages for building logic models from perturbation data and prior knowledge of signalling networks. We have recently developed new components and refined the existing ones. These updates include (i) an Integer Linear Programming (ILP) formulation which guarantees efficient optimisation for Boolean models, (ii) a probabilistic logic implementation for semi-quantitative datasets and (iii) the integration of MaBoSS, a stochastic Boolean simulator. Furthermore, we introduce Dynamic-Feeder, a tool to identify missing links not present in the prior knowledge. We have also implemented systematic post-hoc analyses to highlight the key components and parameters of our models. Finally, we provide an R-Shiny tool to run CellNOpt interactively. AvailabilityR-package(s): https://github.com/saezlab/cellnopt Contactjulio.saez@bioquant.uni-heidelberg.de Supplementary informationSupplemental Text.

bioinformatics↗

bioRxiv2020

Streptococcus pneumoniae infection promotes histone H3 dephosphorylation by modulating host PP1 phosphatase

Pathogenic bacteria can alter host gene expression through post-translational modifications of histones. We show for the first time that a natural colonizer, Streptococcus pneumoniae, also induces specific histone modifications, including robust dephosphorylation of histone H3 on serine 10, during infection of respiratory epithelial cells. Two bacterial factors are important for the induction of this modification: the bacterial toxin PLY, a pore-forming toxin, and the pyruvate oxidase SpxB, an enzyme responsible for H2O2 production. The combined effects of PLY and H2O2 lead to host signaling which culminates in H3S10 dephosphorylation, mediated by the host cell phosphatase PP1. Strikingly, S. pneumoniae infection induces dephosphorylation and associated activation of PP1 catalytic activity. Colonization of cells, which lacked active PP1, resulted in the impairment of intracellular S. pneumoniae survival. Interestingly, PP1 activation mediating H3S10 dephosphorylation is not restricted to S. pneumoniae and appears to be a general epigenomic mechanism favoring intracellular survival.

microbiology↗

bioRxiv2019

Oligogenic effects of 16p11.2 copy number variation on craniofacial development

A copy number variant (CNV) of 16p11.2, which encompasses 30 genes, is associated with developmental and psychiatric disorders, head size and body mass. The genetic mechanisms that underlie these associations are not understood. To elucidate the effects of genes on development, we exploited the quantitative effects of CNV on craniofacial structure in humans and model organisms. We show that reciprocal deletion and duplication of 16p11.2 have characteristic "mirror" effects on craniofacial features that are conserved in human, rat and mouse. By testing gene dosage effects on the shape of the mandible in zebrafish, we show that the distribution of effects for all individual genes is consistent with that of the CNV, and some combinations have non-additive effects. Our results suggest that, at minimum, one third of genes within the 16p11.2 region influence craniofacial development, and the facial gestalt of each CNV represents a product of 30 dosage effects. HighlightsO_LIReciprocal CNVs of 16p11.2 have mirror effects on craniofacial structure. Copy number is associated with a positive effect on nasal and mandibular regions and a negative effect on frontal regions of the face. C_LIO_LIEffects of CNV on craniofacial development in human are well conserved in rat and mouse models of 16p11.2 deletion and duplication. C_LIO_LI7/30 genes each independently have significant effects on the shape of the mandible in zebrafish; these include SPN, C16orf54, SEZ6L2, ASPHD1, TAOK2, INO80E and FAM57B. Others (MAPK3, MVP, KCTD13) have detectable effects only in combination. C_LIO_LIOverexpression of 30 genes individually showed a distribution of effects that was skewed in the same direction as that of the full duplication, suggesting that specific facial features represent the net of all individual effects combined. C_LI

genetics↗

bioRxiv2018

NK cells acquire epigenetic memory of LPS-induced systemic inflammation

Natural killer cells are unique mediators of innate immunity, and as such, an attractive target for immunotherapy. Following viral infection, NK cells display immune memory properties, defined by heightened responses to re-stimulation, an expansion of specific NK cell sup-populations and a protective role against re-infection. However, similar memory to bacterial infection or systemic inflammation, and the molecular mechanisms behind NK cell memory remain elusive. Here we show that following LPS-induced endotoxemia in mice, NK cells acquire cell-intrinsic memory properties as displayed by an amplified production of IFN{gamma} upon secondary stimulation. NK cell memory is acquired even under the post-endotoxemic suppressive environment and is detectable for at least 9 weeks. Furthermore, we define an epigenetic mechanism essential for NK cell memory, where an H3K4me1-marked latent enhancer is uncovered at the ifng locus. Chemical inhibition of histone methyltransferase activity erased the enhancer and prevented NK cells from acquiring memory. Thus, NK cells develop memory to LPS during endotoxemia, in a histone methylation-dependent manner, which ensures a heightened response to secondary stimulation and confers protection against bacterial infection.

immunology↗

bioRxiv2018

Functional characterization of Arabidopsis ARGONAUTE 3 in reproductive tissue

Arabidopsis encodes ten ARGONAUTE (AGO) effectors of RNA silencing, canonically loaded with either 21-22nt small RNAs (sRNA) to mediate post-transcriptional-gene-silencing (PTGS) or 24nt sRNAs to promote RNA-directed-DNA-methylation. Using full-locus constructs, we characterized the expression, biochemical properties, and possible modes of action of AGO3. Although AGO3 arose from a recent duplication at the AGO2 locus, their expression differs drastically, with AGO2 being expressed in both male and female gametes whereas AGO3 accumulates in aerial vascular terminations and specifically in chalazal seed integuments. Accordingly, AGO3 down-regulation alters gene expression in siliques. Similar to AGO2, AGO3 binds sRNAs with a strong 5-adenosine bias, but unlike most Arabidopsis AGOs - AGO2 included - it binds efficiently both 24nt and 21nt sRNAs. AGO3 immunoprecipitation experiments in siliques revealed that these sRNAs mostly correspond to genes and intergenic regions. in a manner reflecting their respective accumulation from their loci-of-origin. AGO3 localizes to the cytoplasm and co-fractionates with polysomes to possibly mediate PTGS via translation inhibition.\n\nSignificance statementThe regulation of gene expression by small RNAs is key for proper plant development and defense. Here, we characterize Arabidopsis AGO3 expression pattern, microRNA regulation and biochemical properties during sexual reproduction.

plant biology↗

bioRxiv2018

BIN1 genetic risk factor for Alzheimer is sufficient to induce early structural tract alterations in entorhinal cortex-dentate gyrus pathway and related hippocampal multi-scale impairments

Genetic factors are known to contribute to Late Onset Alzheimers disease (LOAD) but their contribution to pathophysiology, specially to prodomic phases accessible to therapeutic approaches are far to be understood. To translate genetic risk of Alzheimers disease (AD) into mechanistic insight, we generated transgenic mouse lines that express a [~]195 kbp human BAC that includes only BIN1, a gene associated to LOAD. This model gives a modest BIN1 overexpression, dependent of the number of BAC copies. At 6 months of age, we detected impaired entorhinal cortex (EC)-hippocampal pathways with specific impairments in EC-dentate gyrus synaptic long-term potentiation, dendritic spines of granular cells and recognition episodic memory. Structural changes were quantified using MRI. Their whole-brain functional impact were analyzed using resting state fMRI with a hypoconnectivity centered on entorhinal cortex. These early phenotype defects independent of any changes in A-beta can be instrumental in the search for new AD drug targets.

neuroscience↗