Biology subjects

Boyer, L.

Publications and source records attributed to Boyer, L..

12 recordsLinked to original sources

bioRxiv2026

A TAK1-Driven NLRP1 Inflammasome Pathway Revealed by Phosphatase-Targeting Environmental Toxins

Human NLRP1 is highly sensitive to phosphorylation-dependent activation, indicating a need for tight phosphatase control to prevent excessive inflammasome activity. In this study, we identified the phosphatases PP1 and PP2A as negative regulators of the NLRP1 inflammasome in human keratinocytes. Accordingly, exposure to the environmental toxins Dinophysistoxin, Okadaic acid, and Cantharidin, which inhibit PP1 and PP2A, triggered NLRP1 inflammasome activation. Notably, this toxin-induced activation process relied on hyperactivation of the MAP3 kinase TAK1. Mechanistically, both TAK1 and its downstream effectors p38 kinases phosphorylated and activated the NLRP1 inflammasome. Further studies underscored that TAK1 also contributed to the NLRP1 inflammasome activation during double-stranded RNA stimulation and viral infection. Finally, human native skins exposed to environmental toxins underlined the role of the PP1/PP2A-regulated TAK1/p38 axis in the development of skin dermatitis. Thus, these findings reveal a novel pathway of phosphorylation-driven NLRP1 activation and expand our understanding of its regulation in epithelial immunity. One Sentence SummaryPP1/PP2A phosphatases restrict TAK1-driven NLRP1 inflammasome response. O_FIG O_LINKSMALLFIG WIDTH=146 HEIGHT=200 SRC="FIGDIR/small/701233v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@128de37org.highwire.dtl.DTLVardef@151fbdorg.highwire.dtl.DTLVardef@d6b98aorg.highwire.dtl.DTLVardef@12f419d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO Schematic representation of the phosphorylation-driven hNLRP1 inflammasome response upon exposure to environmental toxins and to dsRNA/viral infection. C_FIG

immunology↗

bioRxiv2025

Targeting p16INK4a reverses alveolar epithelial cell dysfunction and induces lung regeneration in emphysema

Pulmonary emphysema involves impaired regenerative capacity of alveolar type 2 epithelial cells (AT2), the main progenitor cells in alveoli. However, the mechanisms underlying dysfunctional epithelial repair remain unclear. In a mouse model of elastase-induced emphysema, we observed an accumulation of activated AT2s in the lung, associated with an overexpression of p16INK4a (p16), a cell cycle inhibitor known to influence stem cell fate. Deletion of p16 promoted the transition of AT2 into alveolar type 1 (AT1) cells, resulting in tissue regeneration in both mice and alveolar organoids. Pharmacological targeting of the p16 pathway using senolytic agents recapitulate this regenerative effect, further supporting the role of p16 as a key brake on epithelial plasticity. These findings demonstrate that alveolar epithelial cell dysfunction can be reversed by p16 deletion or by eliminating p16+ cells, thereby reactivating the AT2-to-AT1 transition and promoting endogenous alveolar regeneration. This work identifies the p16 pathway as a promising therapeutic target for restoring damaged alveoli in emphysema.

cell biology↗

bioRxiv2025

EASYstrata: a new workflow to infer evolutionary strata along sex chromosomes and other supergenes

New reference genomes and transcriptomes are increasingly available across the tree of life, opening new avenues to tackle exciting questions. However, there are still challenges associated with annotating genomes and inferring evolutionary processes and with a lack of methodological standardisation. Here, we propose a new workflow designed for evolutionary analyses to overcome these challenges, facilitating the detection of recombination suppression and its consequences in terms of rearrangements and transposable element accumulation. To do so, we assemble multiple bioinformatic steps in a single easy-to-use workflow. We combine state-of-the-art tools to detect transposable elements, annotate genomes, infer gene orthology relationships, compute divergence between sequences, infer evolutionary strata (i.e., footprints of stepwise extension of recombination suppression) and their structural rearrangements, and visualise the results. This workflow, called EASYstrata, was applied to reannotate 42 published genomes from Microbotryum fungi. We show in further case examples from a plant and an animal that we recover the same strata as previously described. While this tool was developed with the goal to infer divergence between sex or mating-type chromosomes, it can be applied to any pair of haplotypes whose patteern of divergence is of interest. This workflow will facilitate the study of non-model species for which newly sequenced phased diploid genomes are becoming available. Contactquentinrougemont@orange.fr

genomics↗

bioRxiv2024

Repeated loss of function at HD mating-type genes and of recombination suppression without mating-type locus linkage in anther-smut fungi

A wide diversity of mating systems occur in nature, with frequent evolutionary transitions in mating-compatibility mechanisms. Basidiomycete fungi typically have two mating-type loci controlling mating compatibility, HD and PR, usually residing on different chromosomes. In Microbotryum anther-smut fungi, there have been repeated events of linkage between the two mating-type loci through chromosome fusions, leading to large non-recombining regions. By generating high-quality genome assemblies, we found that two sister Microbotryum species parasitizing Dianthus plants, M. superbum and M. shykoffianum, as well as the distantly related M. scorzonarae, have their HD and PR mating-type loci on different chromosomes, but with the PR mating-type chromosome fused with part of the ancestral HD chromosome. Furthermore, progressive extensions of recombination suppression have generated evolutionary strata. In all three species, rearrangements suggest the existence of a transient stage of HD-PR linkage by whole chromosome fusion, and, unexpectedly, the HD genes lost their function. In M. superbum, multiple natural diploid strains were homozygous, and the disrupted HD2 gene was hardly expressed. Mating tests confirmed that a single genetic factor controlled mating compatibility (i.e. PR) and that haploid strains with identical HD alleles could mate and produce infectious hyphae. The HD genes have therefore lost their function in the control of mating compatibility in these Microbotryum species. While the loss of function of PR genes in mating compatibility has been reported in a few basidiomycete fungi, these are the first documented cases for the loss of mating-type determination by HD genes in heterothallic fungi. The control of mating compatibility by a single genetic factor is beneficial under selfing and can thus be achieved repeatedly, through evolutionary convergence in distant lineages, involving different genomic or similar pathways.

evolutionary biology↗

bioRxiv2023

Ingestion of Bacillus cereus spores dampens the immune response to favor bacterial persistence

Spores are considered as dormant entities highly resistant to extreme conditions. Among them, Bacillus cereus spores are commonly associated with foodborne outbreaks. Nevertheless, the pathological processes associated with spore ingestion and germination remain poorly understood. Here, we show that while ingestion of vegetative bacteria leads to their elimination from the midgut and small intestines of Drosophila and mice, respectively, a single ingestion of spores leads to the persistence of bacteria for at least 10 days. Using Drosophila genetics, we demonstrate that spores escape the innate immune response of the anterior midgut. Once in the posterior midgut, spores germinate, and the vegetative cells dampen the immune signaling through the induction of amidases which are negative regulators of the immune response. This study provides evidence for how B. cereus spores hijack the intestinal immune defenses allowing the localized birth of vegetative bacteria responsible for the digestive symptoms associated with foodborne illness outbreaks.

immunology↗

bioRxiv2023

Temperature and food chain length, but not latitude, explain region-specific kelp forest responses to an unprecedented heatwave

Kelp forests are among the most abundant coastal marine habitats but are vulnerable to the impacts of climate change. Between 2014 and 2016, an unprecedented heatwave and associated changes in trophic dynamics threatened kelp forests across the Northeast Pacific, with impacts documented from Mexico to Alaska. However, responses have varied substantially and remain poorly characterized across large stretches of coast, especially British Columbia (B.C.), which represents a significant percentage of the range of floating kelp species in the Northeast Pacific. Here, we explore variation in floating kelp (Macrocystis, Nereocystis) persistence pre- and post-heatwave across a >675 km latitudinal gradient, asking whether B.C. kelp forests are of conservation concern. We assembled and analyzed available quantitative kelp data, comparing snapshots of kelp extent before (1994 - 2007) and after (2018 - 2021) the heatwave in 11 regions spanning a range of temperature and sea otter-occupancy statuses, and contextualizing these with time series analyses, where available (n = 7 regions). We provide strong evidence that kelp forests have declined in many regions but with evidence of refugia at both local and regional scales. Kelp forest persistence was negatively correlated with summer sea temperatures in southern B.C., where temperatures varied by ~6{degrees}C across sites, at times exceeding species thermal tolerances. Kelp dynamics in northern regions appeared instead to be modulated by top-down control by urchins and sea otters. Our results demonstrate that B.C.s kelp forest have been substantially reduced in recent years but that regional and local-scale factors influence the resilience of forests to large-scale perturbations.

ecology↗

bioRxiv2022

Rapid and Live-cell Detection of Senescence in Mesenchymal Stem Cells by Micro Magnetic Resonance Relaxometry

Detection of cellular senescence is important quality analytics for cell therapy products, including mesenchymal stromal cells (MSCs). However, their detection is critically limited by the lack of specific markers and the destructive assays used to read out these markers. Here, we establish a rapid, live-cell assay for detecting senescent cells using heterogeneous mesenchymal stromal cell (MSC) cultures. We report that the T2 relaxation time measured by microscale Magnetic Resonance Relaxometry ({micro}MRR), which is related to intracellular iron accumulation, correlates strongly with senescent markers in MSC cultures under diverse conditions including different passages and donors, size-sorted MSCs by inertial spiral microfluidic device, and drug-induced senescence. In addition, the live-cell and non-destructive method presented here has general applicability to other cells and tissues, and can critically advance our understanding of cellular senescence.

biophysics↗

bioRxiv2022

Asexual male production by ZW recombination in Artemia parthenogenetica

In some asexual species, parthenogenetic females occasionally produce males, which may strongly affect the evolution and maintenance of asexuality if they cross with related sexuals and transmit genes causing asexuality to their offspring ("contagious parthenogenesis"). How these males arise in the first place has remained enigmatic, especially in species with sex chromosomes. Here, we test the hypothesis that rare, asexually produced males of the crustacean Artemia parthenogenetica are produced by recombination between the Z and W sex chromosomes during non-clonal parthenogenesis, resulting in ZZ males through loss of heterozygosity at the sex determination locus. We used RAD-sequencing to compare asexual mothers with their male and female offspring. Markers on several sex-chromosome scaffolds indeed lost heterozygosity in all male but no female offspring, suggesting that they correspond to the sex-determining region. Other sex-chromosome scaffolds lost heterozygosity in only a part of the male offspring, consistent with recombination occurring at a variable location. Alternative hypotheses for the production of these males (such as partial or total hemizygosity of the Z) could be excluded. Rare males are thus produced because recombination is not entirely suppressed during parthenogenesis in A. parthenogenetica. This finding may contribute to explaining the maintenance of recombination in these asexuals.

evolutionary biology↗

bioRxiv2022

FGF10 triggers de novo alveologenesis in a BPD model: impact on the resident mesenchymal niche cells

Bronchopulmonary dysplasia (BPD) is a neonatal lung disease developing in premature babies characterized by arrested alveologenesis and associated with decreased Fibroblast growth factor 10 (FGF10) expression. One-week hyperoxia (HYX) exposure of newborn mice leads to a permanent arrest in alveologenesis. To test the role of Fgf10 signaling to promote de novo alveologenesis following hyperoxia, we used transgenic mice allowing inducible expression of Fgf10 and recombinant FGF10 (rFGF10) protein delivered intraperitoneally. We carried out morphometry analysis, and IF on day 45. Alveolospheres assays were performed co-culturing AT2s from normoxia (NOX) with FACS-isolated Sca1Pos resident mesenchymal cells (rMC) from animals exposed to NOX, HYX+PBS, or HYX+FGF10. scRNAseq between rMC-Sca1Pos isolated from NOX and HYX+PBS were also carried out. Transgenic overexpression of Fgf10 and rFGF10 administration rescued the alveologenesis defects following HYX. Alveolosphere assays indicate that the activity of rMC-Sca1Pos is negatively impacted by HYX and partially rescued by rFGF10 treatment. Analysis by IF demonstrates a significant impact of rFGF10 on the activity of resident mesenchymal cells. scRNAseq results identified clusters expressing Fgf10, Fgf7, Pdgfra, and Axin2, which could represent the rMC niche cells for the AT2 stem cells. In conclusion, we demonstrate that rFGF10 administration is able to induce de-novo alveologenesis in a BPD mouse model and identified subpopulations of rMC-Sca1Pos niche cells potentially representing its cellular target.

cell biology↗

bioRxiv2021

The origin of asexual brine shrimps

Determining how and how often asexual lineages emerge within sexual species is central to our understanding of sex-asex transitions and the long-term maintenance of sex. Asexuality can arise "by transmission" from an existing asexual lineage to a new one, through different types of crosses. The occurrence of these crosses, cryptic sex, variation in ploidy and recombination within asexuals greatly complicates the study of sex-asex transitions, as they preclude the use of standard phylogenetic methods and genetic distance metrics. In this study we show how to overcome these challenges by developing new approaches to investigate the origin of the various asexual lineages of the brine shrimp Artemia parthenogenetica. We use a large sample of asexuals, including all known polyploids, and their sexual relatives. We combine flow cytometry with mitochondrial and nuclear DNA data. We develop new genetic distance measures and methods to compare various scenarios describing the origin of the different lineages. We find that all diploid and polyploid A. parthenogenetica likely arose within the last 80,000 years through successive and nested hybridization events that involved backcrosses with different sexual species. All A. parthenogenetica have the same common ancestor and therefore likely carry the same asexuality gene(s) and reproduce by automixis. These findings radically change our view of sex-asex transitions in this group, and show the importance of considering asexuality "by transmission" scenarios. The methods developed are applicable to many other asexual taxa.

evolutionary biology↗

bioRxiv2020

Cell size is a determinant of stem cell potential during aging

Stem cells are remarkably small in size. Whether small size is important for stem cell function is unknown. We find that murine hematopoietic stem cells (HSCs) enlarge under conditions known to decrease stem cell function. This decreased fitness of large HSCs is due to reduced proliferative potential. Preventing HSC enlargement by inhibiting macromolecule biosynthesis or reducing large HSCs size by shortening G1 averts the loss of stem cell potential under conditions causing stem cell exhaustion. Finally, we show that a fraction of murine and human HSCs enlarge during aging. Preventing this age-dependent enlargement improves HSC function. We conclude that small cell size is important for stem cell function in vivo and propose that stem cell enlargement contributes to their functional decline during aging. One Sentence SummarySize increase drives stem cell aging.

cell biology↗

bioRxiv2020

A dual role for H2A.Z.1 in modulating the dynamics of RNA Polymerase II initiation and elongation

RNAPII pausing immediately downstream of the transcription start site (TSS) is a critical rate limiting step at most metazoan genes that allows fine-tuning of gene expression in response to diverse signals1-5. During pause-release, RNA Polymerase II (RNAPII) encounters an H2A.Z.1 nucleosome6-8, yet how this variant contributes to transcription is poorly understood. Here, we use high resolution genomic approaches2,9 (NET-seq and ChIP-nexus) along with live cell super-resolution microscopy (tcPALM)10 to investigate the role of H2A.Z.1 on RNAPII dynamics in embryonic stem cells (ESCs). Using a rapid, inducible protein degron system11 combined with transcriptional initiation and elongation inhibitors, our quantitative analysis shows that H2A.Z.1 slows the release of RNAPII, impacting both RNAPII and NELF dynamics at a single molecule level. We also find that H2A.Z.1 loss has a dramatic impact on nascent transcription at stably paused, signal-dependent genes. Furthermore, we demonstrate that H2A.Z.1 inhibits re-assembly and re-initiation of the PIC to reinforce the paused state and acts as a strong additional pause signal at stably paused genes. Together, our study suggests that H2A.Z.1 fine-tunes gene expression by regulating RNAPII kinetics in mammalian cells.

genomics↗