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The last 50 bibliographies

A Perspective for Ménière's Disease: In Silico Investigations of Dexamethasone as a Direct Modulator of AQP2.

Author(s) : Mom R, Robert-Paganin J, Mom T, Chabbert C, Réty S, Auguin D,
Journal : Biomolecules
2022
Ménière's disease is a chronic illness characterized by intermittent episodes ofvertigo associated with fluctuating sensorineural hearing loss, tinnitus andaural pressure. This pathology strongly correlates with a dilatation of the fluidcompartment of the endolymph, so-called hydrops. Dexamethasone is one of thetherapeutic approaches recommended when conventional antivertigo treatments havefailed. Several mechanisms of actions have been hypothesized for the mode ofaction of dexamethasone, such as the anti-inflammatory effect or as a regulatorof inner ear water homeostasis. However, none of them have been experimentallyconfirmed so far. Aquaporins (AQPs) are transmembrane water channels and arehence central in the regulation of transcellular water fluxes. In the presentstudy, we investigated the hypothesis that dexamethasone could impact waterfluxes in the inner ear by targeting AQP2. We addressed this question throughmolecular dynamics simulations approaches and managed to demonstrate a directinteraction between AQP2 and dexamethasone and its significant impact on thechannel water permeability. Through compartmentalization of sodium and potassiumions, a significant effect of Na+ upon AQP2 water permeability was highlighted aswell. The molecular mechanisms involved in dexamethasone binding and in itsregulatory action upon AQP2 function are described.

3DGenBench: a web-server to benchmark computational models for 3D Genomics.

Author(s) : Belokopytova P, Viesná E, Chiliński M, Qi Y, Salari H, Di Stefano M, Esposito A, Conte A, Chiariello A, Teif V, Plewczynski D, Zhang B, Jost D, Fishman V,
Journal : Nucleic Acids Res
2022
Modeling 3D genome organisation has been booming in the last years thanks to theavailability of experimental datasets of genomic contacts. However, the field iscurrently missing the standardisation of methods and metrics to comparepredictions and experiments. We present 3DGenBench, a web server available athttps://inc-cost.eu/benchmarking/, that allows benchmarking computational modelsof 3D Genomics. The benchmark is performed using a manually curated dataset of 39capture Hi-C profiles in wild type and genome-edited mouse cells, and fivegenome-wide Hi-C profiles in human, mouse, and Drosophila cells. 3DGenBenchperforms two kinds of analysis, each supplied with a specific scoring module thatcompares predictions of a computational method to experimental data using severalmetrics. With 3DGenBench, the user obtains model performance scores, allowing anunbiased comparison with other models. 3DGenBench aims to become a reference webserver to test new 3D genomics models and is conceived as an evolving platformwhere new types of analysis will be implemented in the future.

FORK-seq: Single-Molecule Profiling of DNA Replication.

Author(s) : Hennion M, Theulot B, Arbona J, Audit B, Hyrien O,
Journal : Methods Mol Biol
2022
Most genome replication mapping methods profile cell populations, maskingcell-to-cell heterogeneity. Here, we describe FORK-seq, a nanopore sequencingmethod to map replication of single DNA molecules at 200 nucleotide resolutionusing a nanopore current interpretation tool allowing the quantification of BrdUincorporation. Along pulse-chased replication intermediates from Saccharomycescerevisiae, we can orient replication tracks and reproduce population-basedreplication directionality profiles. Additionally, we can map individualinitiation and termination events. Thus, FORK-seq reveals the full extent ofcell-to-cell heterogeneity in DNA replication.

Genome-wide mapping of individual replication fork velocities using nanopore sequencing.

Author(s) : Theulot B, Lacroix L, Arbona J, Millot G, Jean E, Cruaud C, Pellet J, Proux F, Hennion M, Engelen S, Lemainque A, Audit B, Hyrien O, Le Tallec B,
Journal : Nat Commun
2022
Little is known about replication fork velocity variations along eukaryoticgenomes, since reference techniques to determine fork speed either provide nosequence information or suffer from low throughput. Here we presentNanoForkSpeed, a nanopore sequencing-based method to map and extract the velocityof individual forks detected as tracks of the thymidine analoguebromodeoxyuridine incorporated during a brief pulse-labelling of asynchronouslygrowing cells. NanoForkSpeed retrieves previous Saccharomyces cerevisiae meanfork speed estimates (≈2 kb/min) in the BT1 strain exhibiting highly efficientbromodeoxyuridine incorporation and wild-type growth, and precisely quantifiesspeed changes in cells with altered replisome progression or exposed tohydroxyurea. The positioning of >125,000 fork velocities provides a genome-widemap of fork progression based on individual fork rates, showing a uniform forkspeed across yeast chromosomes except for a marked slowdown at known pausingsites.

Titration of Apparent In-Cellula Affinities of Protein-Protein Interactions.

Author(s) : Cluet D, Vergier B, Levy N, Dehau L, Thurman A, Amri I, Spichty M,
Journal : Chembiochem
2022
A genetic assay permits simultaneous quantification of two interacting proteinsand their bound fraction at the single-cell level using flow cytometry. Apparentin-cellula affinities of protein-protein interactions can be extracted from theacquired data through a titration-like analysis. The applicability of thisapproach is demonstrated on a diverse set of interactions with proteins fromdifferent families and organisms and with in-vitro dissociation constants rangingfrom picomolar to micromolar.

Prognostic impact of ABCA3 expression in adult and pediatric acute myeloid leukemia: an ALFA-ELAM02 joint study

Author(s) : Ceraulo A, Lapillonne H, Cheok M, Preudhomme C, Dombret H, Terré C, Lambert J, Leverger G, Bertrand Y, Mortreux F, Wattel E,
Journal : Blood Adv
2022

Evolutionary divergence of anaphase spindle mechanics in nematode embryos constrained by antagonistic pulling and viscous forces.

Author(s) : Khatri D, Brugière T, Athale C, Delattre M,
Journal : Mol Biol Cell
2022
Cellular functions like cell division are remarkably conserved across phyla.However the evolutionary principles of cellular organization that drive it areless well explored. Thus, an essential question remains: to what extent cellularparameters evolve without altering the basic function they sustain? Here we haveobserved 6 different nematode species for which the mitotic spindle is positionedasymmetrically during the first embryonic division. Whereas the C. elegansspindle undergoes oscillations during its displacement, the spindle elongateswithout oscillations in other species. We asked which evolutionary changes inbiophysical parameters could explain differences in spindle motion whilemaintaining a constant output. Using laser microsurgery of the spindle werevealed that all species are subjected to cortical pulling forces, of varyingmagnitudes. Using a viscoelastic model to fit the recoil trajectories and with anindependent measurement of cytoplasmic viscosity, we extracted the values ofcytoplasmic drag, cortical pulling forces and spindle elasticity for all species.We found large variations in cytoplasmic viscosity whereas cortical pullingforces and elasticity were often more constrained. In agreement with previoussimulations, we found that increased viscosity correlates with decreasedoscillation speeds across species. However, the absence of oscillations despitelow viscosity in some species, can only be explained by smaller pulling forces.Consequently, we find that spindle mobility across the species analyzed here ischaracterized by a tradeoff between cytoplasmic viscosity and pulling forcesnormalized by the size of the embryo. Our work provides a framework forunderstanding mechanical constraints on evolutionary diversification of spindlemobility.

Paternal transmission of the Wolbachia CidB toxin underlies cytoplasmic incompatibility.

Author(s) : Horard B, Terretaz K, Gosselin-Grenet A, Sobry H, Sicard M, Landmann F, Loppin B,
Journal : Curr Biol
2022
Wolbachia are widespread endosymbiotic bacteria that manipulate the reproduction ofarthropods through a diversity of cellular mechanisms. In cytoplasmicincompatibility (CI), a sterility syndrome originally discovered in the mosquitoCulex pipiens, uninfected eggs fertilized by sperm from infected males areselectively killed during embryo development following the abortive segregation ofpaternal chromosomes in the zygote. Despite the recent discovery of Wolbachia CIfactor (cif) genes, the mechanism by which they control the fate of paternalchromosomes at fertilization remains unknown. Here, we have analyzed the cytologicaldistribution and cellular impact of CidA and CidB, a pair of Cif proteins from theCulex-infecting Wolbachia strain wPip. We show that expression of CidB in DrosophilaS2R+ cells induces apoptosis unless CidA is co-expressed and associated with itspartner. In transgenic Drosophila testes, both effectors colocalize in germ cellsuntil the histone-to-protamine transition in which only CidB is retained in maturingspermatid nuclei. We further show that CidB is similarly targeted to maturing spermof naturally infected Culex mosquitoes. At fertilization, CidB associates withpaternal DNA regions exhibiting DNA replication stress, as a likely cause ofincomplete replication of paternal chromosomes at the onset of the first mitosis.Importantly, we demonstrate that inactivation of the deubiquitylase activity of CidBdoes not abolish its cell toxicity or its ability to induce CI in Drosophila. Ourstudy thus demonstrates that CI functions as a transgenerational toxin-antidotesystem and suggests that CidB acts by poisoning paternal DNA replication inincompatible crosses.

Three classes of epigenomic regulators converge to hyperactivate the essential maternal gene deadhead within a heterochromatin mini-domain.

Author(s) : Torres-Campana D, Horard B, Denaud S, Benoit G, Loppin B, Orsi G,
Journal : PLoS Genet
2022
The formation of a diploid zygote is a highly complex cellular process that isentirely controlled by maternal gene products stored in the egg cytoplasm. Thishighly specialized transcriptional program is tightly controlled at the chromatinlevel in the female germline. As an extreme case in point, the massive and specificovarian expression of the essential thioredoxin Deadhead (DHD) is criticallyregulated in Drosophila by the histone demethylase Lid and its partner, the histonedeacetylase complex Sin3A/Rpd3, via yet unknown mechanisms. Here, we identified Snr1and Mod(mdg4) as essential for dhd expression and investigated how these epigenomiceffectors act with Lid and Sin3A to hyperactivate dhd. Using Cut&Run chromatinprofiling with a dedicated data analysis procedure, we found that dhd isintriguingly embedded in an H3K27me3/H3K9me3-enriched mini-domain flanked by DNAregulatory elements, including a dhd promoter-proximal element essential for itsexpression. Surprisingly, Lid, Sin3a, Snr1 and Mod(mdg4) impact H3K27me3 and thisregulatory element in distinct manners. However, we show that these effectorsactivate dhd independently of H3K27me3/H3K9me3, and that dhd remains silent in theabsence of these marks. Together, our study demonstrates an atypical and criticalrole for chromatin regulators Lid, Sin3A, Snr1 and Mod(mdg4) to triggertissue-specific hyperactivation within a unique heterochromatin mini-domain.

Spatial organization of chromosomes leads to heterogeneous chromatin motion and drives the liquid- or gel-like dynamical behavior of chromatin.

Author(s) : Salari H, Di Stefano M, Jost D,
Journal : Genome Res
2022
Chromosome organization and dynamics are involved in regulating many fundamentalprocesses such as gene transcription and DNA repair. Experiments unveiled thatchromatin motion is highly heterogeneous inside cell nuclei, ranging from aliquid-like, mobile state to a gel-like, rigid regime. Using polymer modeling, weinvestigate how these different physical states and dynamical heterogeneities mayemerge from the same structural mechanisms. We found that the formation oftopologically associating domains (TADs) is a key driver of chromatin motionheterogeneity. In particular, we showed that the local degree of compaction of theTAD regulates the transition from a weakly compact, fluid state of chromatin to amore compact, gel state exhibiting anomalous diffusion and coherent motion. Our workprovides a comprehensive study of chromosome dynamics and a unified view ofchromatin motion enabling interpretation of the wide variety of dynamical behaviorsobserved experimentally across different biological conditions, suggesting that the"liquid" or "solid" state of chromatin are in fact two sides of the same coin.