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Reduction of a stochastic model of gene expression: Lagrangian dynamics gives access to basins of attraction as cell types and metastabilty

Author(s) : Ventre E, Espinasse T, hier C, Calvez V, Lepoutre T, Gandrillon O,
Journal : J Math Biol

Ribosome dynamics and mRNA turnover, a complex relationship under constant cellular scrutiny.

Author(s) : Morris C, Cluet D, Ricci E,
Journal : Wiley Interdiscip Rev RNA
Eukaryotic gene expression is closely regulated by translation and turnover ofmRNAs. Recent advances highlight the importance of translation in the control ofmRNA degradation, both for aberrant and apparently normal mRNAs. During translation,the information contained in mRNAs is decoded by ribosomes, one codon at a time, andtRNAs, by specifically recognizing codons, translate the nucleotide code into aminoacids. Such a decoding step does not process regularly, with various obstacles thatcan hinder ribosome progression, then leading to ribosome stalling or collisions.The progression of ribosomes is constantly monitored by the cell which has evolvedseveral translation-dependent mRNA surveillance pathways, includingnonsense-mediated decay (NMD), no-go decay (NGD), and non-stop decay (NSD), todegrade certain problematic mRNAs and the incomplete protein products. Recentprogress in sequencing and ribosome profiling has made it possible to discover newmechanisms controlling ribosome dynamics, with numerous crosstalks betweentranslation and mRNA decay. We discuss here various translation features criticalfor mRNA decay, with particular focus on current insights from the complexity of thegenetic code and also the emerging role for the ribosome as a regulatory huborchestrating mRNA decay, quality control, and stress signaling. Even if theinterplay between mRNA translation and degradation is no longer to be demonstrated,a better understanding of their precise coordination is worthy of furtherinvestigation. This article is categorized under: RNA Turnover and Surveillance >Regulation of RNA Stability Translation > Translation Regulation RNA Interactionswith Proteins and Other Molecules > RNA-Protein Complexes.

RNA polymerase backtracking results in the accumulation of fission yeast condensin at active genes.

Author(s) : Rivosecchi J, Jost D, Vachez L, Gautier F, Bernard P, Vanoosthuyse V,
Journal : Life Sci Alliance
The mechanisms leading to the accumulation of the SMC complexes condensins aroundspecific transcription units remain unclear. Observations made in bacteria suggestedthat RNA polymerases (RNAPs) constitute an obstacle to SMC translocation,particularly when RNAP and SMC travel in opposite directions. Here we show infission yeast that gene termini harbour intrinsic condensin-accumulating featureswhatever the orientation of transcription, which we attribute to the frequentbacktracking of RNAP at gene ends. Consistent with this, to relocate backtrackedRNAP2 from gene termini to gene bodies was sufficient to cancel the accumulation ofcondensin at gene ends and to redistribute it evenly within transcription units,indicating that RNAP backtracking may play a key role in positioning condensin.Formalization of this hypothesis in a mathematical model suggests that the inclusionof a sub-population of RNAP with longer dwell-times is essential to fullyrecapitulate the distribution profiles of condensin around active genes. Takentogether, our data strengthen the idea that dense arrays of proteins tightly boundto DNA alter the distribution of condensin on chromosomes.

Shaping the Innate Immune Response Through Post-Transcriptional Regulation of Gene Expression Mediated by RNA-Binding Proteins.

Author(s) : Guillemin A, Kumar A, Wencker M, Ricci E,
Journal : Front Immunol
Innate immunity is the frontline of defense against infections and tissue damage.It is a fast and semi-specific response involving a myriad of processes essentialfor protecting the organism. These reactions promote the clearance of danger byactivating, among others, an inflammatory response, the complement cascade and byrecruiting the adaptive immunity. Any disequilibrium in this functional balancecan lead to either inflammation-mediated tissue damage or defense inefficiency. Adynamic and coordinated gene expression program lies at the heart of the innateimmune response. This expression program varies depending on the cell-type andthe specific danger signal encountered by the cell and involves multiple layersof regulation. While these are achieved mainly via transcriptional control ofgene expression, numerous post-transcriptional regulatory pathways involvingRNA-binding proteins (RBPs) and other effectors play a critical role in itsfine-tuning. Alternative splicing, translational control and mRNA stability havebeen shown to be tightly regulated during the innate immune response andparticipate in modulating gene expression in a global or gene specific manner.More recently, microRNAs assisting RBPs and post-transcriptional modification ofRNA bases are also emerging as essential players of the innate immune process. Inthis review, we highlight the numerous roles played by specific RNA-bindingeffectors in mediating post-transcriptional control of gene expression to shapeinnate immunity.

SISTEMA: A large and standardized collection of transcriptome data sets for human pluripotent stem cell research

Author(s) : Jarrige M, Polvèche H, Carteron A, Janczarski S, Peschanski M, Auboeuf D, Martinat C,
Journal : iScience
Human pluripotent stem cells have ushered in an exciting new era for disease modeling, drug discovery, and cell therapy development. Continued progress toward realizing the potential of human pluripotent stem cells will be facilitated by robust data sets and complementary resources that are easily accessed and interrogated by the stem cell community. In this context, we present SISTEMA, a quality-controlled curated gene expression database, built on a valuable catalog of human pluripotent stem cell lines, and their derivatives for which transcriptomic analyses have been generated using a single experimental pipeline. SISTEMA functions as a one-step resource that will assist the stem cell community to easily evaluate the expression level for genes of interest, while comparing them across different hPSC lines, cell types, pathological conditions, or after pharmacological treatments.

Structural and functional studies of SF1B Pif1 from Thermus oshimai reveal dimerization-induced helicase inhibition.

Author(s) : Dai Y, Chen W, Liu N, Teng F, Guo H, Hou X, Dou S, Rety S, Xi X,
Journal : Nucleic Acids Res
Pif1 is an SF1B helicase that is evolutionarily conserved from bacteria to humansand plays multiple roles in maintaining genome stability in both nucleus andmitochondria. Though highly conserved, Pif1 family harbors a large mechanisticdiversity. Here, we report crystal structures of Thermus oshimai Pif1 (ToPif1)alone and complexed with partial duplex or single-stranded DNA. In the apo stateand in complex with a partial duplex DNA, ToPif1 is monomeric with its domain2B/loop3 adopting a closed and an open conformation, respectively. When complexedwith a single-stranded DNA, ToPif1 forms a stable dimer with domain 2B/loop3shifting to a more open conformation. Single-molecule and biochemical assays showthat domain 2B/loop3 switches repetitively between the closed and openconformations when a ToPif1 monomer unwinds DNA and, in contrast with othertypical dimeric SF1A helicases, dimerization has an inhibitory effect on itshelicase activity. This mechanism is not general for all Pif1 helicases butillustrates the diversity of regulation mechanisms among different helicases. Italso raises the possibility that although dimerization results in activation forSF1A helicases, it may lead to inhibition for some of the other uncharacterizedSF1B helicases, an interesting subject warranting further studies.

Structural study of the function of Candida Albicans Pif1.

Author(s) : Lu K, Xin B, Zhang T, Liu N, Li D, Rety S, Xi X,
Journal : Biochem Biophys Res Commun
Pif1 helicases, conserved in eukaryotes, are involved in maintaining genomestability in both the nucleus and mitochondria. Here, we report the crystalstructure of a truncated Candida Albicans Pif1 (CaPif1(368-883)) in complex withssDNA and an ATP analog. Our results show that the Q-motif is responsible foridentifying adenine bases, and CaPif1 preferentially utilizes ATP/dATP duringdsDNA unwinding. Although CaPif1 shares structural similarities withSaccharomyces cerevisiae Pif1, CaPif1 can contact the thymidine bases of DNA byhydrogen bonds, whereas ScPif1 cannot. More importantly, the crosslinking andmutant experiments have demonstrated that the conformational change of domain 2Bis necessary for CaPif1 to unwind dsDNA. These findings contribute to further theunderstanding of the unwinding mechanism of Pif1.

Terminal modification, sequence, length, and PIWI-protein identity determine piRNA stability

Author(s) : Gainetdinov I, Colpan C, Cecchini K, Arif A, Jouravleva K, Albosta P, Vega-Badillo J, Lee Y, Ozata D, Zamore P,
Journal : Mol Cell
In animals, PIWI-interacting RNAs (piRNAs) silence transposons, fight viral infections, and regulate gene expression. piRNA biogenesis concludes with 3' terminal trimming and 2'-O-methylation. Both trimming and methylation influence piRNA stability. Our biochemical data show that multiple mechanisms destabilize unmethylated mouse piRNAs, depending on whether the piRNA 5' or 3' sequence is complementary to a trigger RNA. Unlike target-directed degradation of microRNAs, complementarity-dependent destabilization of piRNAs in mice and flies is blocked by 3' terminal 2'-O-methylation and does not require base pairing to both the piRNA seed and the 3' sequence. In flies, 2'-O-methylation also protects small interfering RNAs (siRNAs) from complementarity-dependent destruction. By contrast, pre-piRNA trimming protects mouse piRNAs from a degradation pathway unaffected by trigger complementarity. In testis lysate and in vivo, internal or 3' terminal uridine- or guanine-rich tracts accelerate pre-piRNA decay. Loss of both trimming and 2'-O-methylation causes the mouse piRNA pathway to collapse, demonstrating that these modifications collaborate to stabilize piRNAs.

The first steps in the life of a worm: Themes and variations in asymmetric division in C. elegans and other nematodes.

Author(s) : Delattre M, Goehring N,
Journal : Curr Top Dev Biol
Starting with Boveri in the 1870s, microscopic investigation of early embryogenesisin a broad swath of nematode species revealed the central role of asymmetric celldivision in embryonic axis specification, blastomere positioning, and cell fatespecification. Notably, across the class Chromadorea, a conserved themeemerges-asymmetry is first established in the zygote and specifies its asymmetricdivision, giving rise to an anterior somatic daughter cell and a posterior germlinedaughter cell. Beginning in the 1980s, the emergence of Caenorhabditis elegans as amodel organism saw the advent of genetic tools that enabled rapid progress in ourunderstanding of the molecular mechanisms underlying asymmetric division, in manycases defining key paradigms that turn out to regulate asymmetric division in a widerange of systems. Yet, the consequence of this focus on C. elegans came at theexpense of exploring the extant diversity of developmental variation exhibitedacross nematode species. Given the resurgent interest in evolutionary studiesfacilitated in part by new tools, here we revisit the diversity in this asymmetricfirst division, juxtaposing molecular insight into mechanisms of symmetry-breaking,spindle positioning and fate specification, with a consideration of plasticity andvariability within and between species. In the process, we hope to highlightquestions of evolutionary forces and molecular variation that may have shaped theextant diversity of developmental mechanisms observed across Nematoda.

The fluorescent protein stability assay: an efficient method for monitoring intracellular protein stability.

Author(s) : Roisin A, Buchsbaum S, Mocquet V, Jalinot P,
Journal : Biotechniques
The stability of intracellular proteins is highly variable, from a few minutes toseveral hours, and can be tightly regulated to respond to external and internalcellular environment changes. Several techniques can be used to study thestability of a specific protein, including pulse-chase labeling and blocking oftranslation. Another approach that has gained interest in recent years is fusinga protein of interest to a fluorescent reporter. In this report, the authorspresent a new version of this approach aimed at optimizing expression andcomparison of the two reporter proteins. The authors show that the system worksefficiently in various cells and can be useful for studying changes in proteinstability and assessing the effects of drugs.

The HTLV-1 viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape

Author(s) : Vandermeulen C, O'Grady T, Wayet J, Galvan B, Maseko S, Cherkaoui M, Desbuleux A, Coppin G, Olivet J, Ben Ameur L, Kataoka K, Ogawa S, Hermine O, Marcais A, Thiry M, Mortreux F, Calderwood M, Van Weyenbergh J, Peloponese J, Charloteaux B, Van den Broeke A, Hill D, Vidal M, Dequiedt F, Twizere J,
Journal : PLoS Pathog
Viral infections are known to hijack the transcription and translation of the host cell. However, the extent to which viral proteins coordinate these perturbations remains unclear. Here we used a model system, the human T-cell leukemia virus type 1 (HTLV-1), and systematically analyzed the transcriptome and interactome of key effectors oncoviral proteins Tax and HBZ. We showed that Tax and HBZ target distinct but also common transcription factors. Unexpectedly, we also uncovered a large set of interactions with RNA-binding proteins, including the U2 auxiliary factor large subunit (U2AF2), a key cellular regulator of pre-mRNA splicing. We discovered that Tax and HBZ perturb the splicing landscape by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia/lymphoma (ATLL) samples from two independent patient cohorts, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinated by Tax and HBZ to reprogram the transcriptome.

The Physics-Biology continuum challenges darwinism: Evolution is directed by the homeostasis-dependent bidirectional relation between genome and phenotype

Author(s) : Auboeuf D,
Journal : Prog Biophys Mol Biol
The physics-biology continuum relies on the fact that life emerged from prebiotic molecules. Here, I argue that life emerged from the coupling between nucleic acid and protein synthesis during which proteins (or proto-phenotypes) maintained the physicochemical parameter equilibria (or proto-homeostasis) in the proximity of their encoding nucleic acids (or proto-genomes). This protected the proto-genome physicochemical integrity (i.e., atomic composition) from environmental physicochemical constraints, and therefore increased the probability of reproducing the proto-genome without variation. From there, genomes evolved depending on the biological activities they generated in response to environmental fluctuations. Thus, a genome maintaining homeostasis (i.e., internal physicochemical parameter equilibria), despite and in response to environmental fluctuations, maintains its physicochemical integrity and has therefore a higher probability to be reproduced without variation. Consequently, descendants have a higher probability to share the same phenotype than their parents. Otherwise, the genome is modified during replication as a consequence of the imbalance of the internal physicochemical parameters it generates, until new mutation-deriving biological activities maintain homeostasis in offspring. In summary, evolution depends on feedforward and feedback loops between genome and phenotype, as the internal physicochemical conditions that a genome generates ─ through its derived phenotype in response to environmental fluctuations ─ in turn either guarantee its stability or direct its variation. Evolution may not be explained by the Darwinism-derived, unidirectional principle (random mutations-phenotypes-natural selection) but rather by the bidirectional relationship between genome and phenotype, in which the phenotype in interaction with the environment directs the evolution of the genome it derives from.

The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission

Author(s) : Jeanpierre S, Arizkane K, Thongjuea S, Grockowiak E, Geistlich K, Barral L, Voeltzel T, Guillemin A, Gonin-Giraud S, Gandrillon O, Nicolini F, Mead A, Maguer-Satta V, Lefort S,
Journal : Haematologica

Voltage-gating of aquaporins, a putative conserved safety mechanism during ionic stresses.

Author(s) : Mom R, Muries B, Benoit P, Robert-Paganin J, Réty S, Venisse J, Padua A, Label P, Auguin D,
Journal : FEBS Lett
Aquaporins are transmembrane water channels found in almost every livingorganism. Numerous studies have brought a good understanding of both watertransport through their pores and the regulations taking place at the molecularlevel, but subtleties remain to be clarified. Recently, a voltage-related gatingmechanism involving the conserved arginine of the channel's main constriction wascaptured for human aquaporins through molecular dynamics studies. With a similarapproach, we show that this voltage-gating could be conserved among this familyand that the underlying mechanism could explain part of plant AQPs diversity whencontextualized to high ionic concentrations provoked by drought. Finally, weidentified residues as adaptive traits which constitute good targets for droughtresistance plant breeding research.