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A DPP-mediated feed-forward loop canalizes morphogenesis during Drosophila dorsal closure.

Author(s) : Ducuing A, Keeley C, Mollereau B, Vincent S,
Journal : J Cell Biol
Development is robust because nature has selected various mechanisms to buffer the deleterious effects of environmental and genetic variations to deliver phenotypic stability. Robustness relies on smart network motifs such as feed-forward loops (FFLs) that ensure the reliable interpretation of developmental signals. In this paper, we show that Decapentaplegic (DPP) and JNKform a coherent FFL that controls the specification and differentiation of leading edge cells during Drosophila melanogaster dorsal closure (DC). We provide molecular evidence that through repression by Brinker (Brk), the DPP branch of the FFL filters unwanted JNK activity. High-throughput live imaging revealed that this DPP/Brk branch is dispensable for DC under normal conditions but is required when embryos are subjected to thermal stress. Our results indicate that the wiring of DPP signaling buffers against environmental challenges and canalizes cell identity. We propose that the main function of DPP pathway during Drosophila DC is to ensure robust morphogenesis, a distinct function from its well-established ability to spread spatial information.

Adult T-Cell Leukemia/Lymphoma in a Caucasian Patient After Sexual Transmission of Human T-Cell Lymphotropic Virus Type 1.

Author(s) : Sibon D, Cassar O, Duga I, Brouzes C, Ghez D, Pasquier C, Sibon C, Desrames A, Mortreux F, Wattel E, Bazarbachi A, Gessain A, Hermine O,
Journal : Open Forum Infect Dis
Adult T-cell leukemia/lymphoma (ATLL), a T-cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1), develops in the majority of cases in individuals who were infected with HTLV-1 as young children, by their mother during prolonged breastfeeding. We report the case of a Caucasian French man, whose parents were HTLV-1-seronegative and who developed ATLL after HTLV-1 sexual transmission by a Cameroonian woman. This hypothesis was corroborated by genotyping of the patient's virus, which revealed an HTLV-1B strain, found only in Central Africa, especially in Cameroon. Thus, ATLL may develop after HTLV-1 infection during adulthood, outside breastfeeding.

Adult T-Cell Leukemia/Lymphoma in a Caucasian Patient After Sexual Transmission of Human T-Cell Lymphotropic Virus Type 1.

Author(s) : Sibon D, Cassar O, Duga I, Brouzes C, Ghez D, Pasquier C, Sibon C, Desrames A, Mortreux F, Wattel E, Bazarbachi A, Gessain A, Hermine O,
Journal : Open Forum Infect Dis
Adult T-cell leukemia/lymphoma (ATLL), a T-cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1), develops in the majority of cases in individuals who were infected with HTLV-1 as young children, by their mother during prolonged breastfeeding. We report the case of a Caucasian French man, whose parents were HTLV-1-seronegative and who developed ATLL after HTLV-1 sexual transmission by a Cameroonian woman. This hypothesis was corroborated by genotyping of the patient's virus, which revealed an HTLV-1B strain, found only in Central Africa, especially in Cameroon. Thus, ATLL may develop after HTLV-1 infection during adulthood, outside breastfeeding.

An optimized kit-free method for making strand-specific deep sequencing libraries from RNA fragments.

Author(s) : Heyer E, Ozadam H, Ricci E, Cenik C, Moore M,
Journal : Nucleic Acids Res
Deep sequencing of strand-specific cDNA libraries is now a ubiquitous tool for identifying and quantifying RNAs in diverse sample types. The accuracy of conclusions drawn from these analyses depends on precise and quantitative conversion of the RNA sample into a DNA library suitable for sequencing. Here, we describe an optimized method of preparing strand-specific RNA deep sequencing libraries from small RNAs and variably sized RNA fragments obtained from ribonucleoprotein particle footprinting experiments or fragmentation of long RNAs. Our approach works across a wide range of input amounts (400 pg to 200 ng), is easy to follow and produces a library in 2-3 days at relatively low reagent cost, all while giving the user complete control over every step. Because all enzymatic reactions were optimized and driven to apparent completion, sequence diversity and species abundance in the input sample are well preserved.

Chromatids segregate without centrosomes during Caenorhabditis elegans mitosis in a Ran- and CLASP-dependent manner.

Author(s) : Nahaboo W, Zouak M, Askjaer P, Delattre M,
Journal : Mol Biol Cell
During mitosis, chromosomes are connected to a microtubule-based spindle. Current models propose that displacement of the spindle poles and/or the activity of kinetochore microtubules generate mechanical forces that segregate sister chromatids. Using laser destruction of the centrosomes during Caenorhabditis elegans mitosis, we show that neither of these mechanisms is necessary to achieve proper chromatid segregation. Our results strongly suggest that an outward forcegenerated by the spindle midzone, independently of centrosomes, is sufficient tosegregate chromosomes in mitotic cells. Using mutant and RNAi analysis, we show that the microtubule-bundling protein SPD-1/MAP-65 and BMK-1/kinesin-5 act as a brake opposing the force generated by the spindle midzone. Conversely, we identify a novel role for two microtubule-growth and nucleation agents, Ran and CLASP, in the establishment of the centrosome-independent force during anaphase.Their involvement raises the interesting possibility that microtubule polymerization of midzone microtubules is continuously required to sustain chromosome segregation during mitosis.

Cooling-Induced ER Stress is Good for Your Brain.

Author(s) : Mollereau B,
Journal : EBioMedicine

Discovery and characterization of auxiliary proteins encoded by type 3 simian T-cell lymphotropic viruses.

Author(s) : Turpin J, Journo C, Ko N, Sinet F, Carpentier A, Galioot A, Edwards D, Vandamme A, Gazzolo L, Duc Dodon M, Gessain A, Kashanchi F, Balansard I, Lacoste R, Mahieux R,
Journal : J Virol
Human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2 encode auxiliary proteins that play important roles in viral replication, viral latency, and immune escape. The presence of auxiliary protein-encoding open reading frames (ORFs) in HTLV-3, the latest HTLV to be discovered, is unknown. Simian T-cell lymphotropic virus type 3 (STLV-3) is almost identical to HTLV-3. Given the lackof HTLV-3-infected cell lines, we took advantage of STLV-3-infected cells and ofan STLV-3 molecular clone to search for the presence of auxiliary transcripts. Using reverse transcriptase PCR (RT-PCR), we first uncovered the presence of three unknown viral mRNAs encoding putative proteins of 5, 8, and 9 kDa and confirmed the presence of the previously reported RorfII transcript. The existence of these viral mRNAs was confirmed by using splice site-specific RT-PCR with ex vivo samples. We showed that p5 is distributed throughout the cell and does not colocalize with a specific organelle. The p9 localization is similar tothat of HTLV-1 p12 and induced a strong decrease in the calreticulin signal, similarly to HTLV-1 p12. Although p8, RorfII, and Rex-3 share an N-terminal sequence that is predicted to contain a nucleolar localization signal (NoLS), only p8 is found in the nucleolus. The p8 location in the nucleolus is linked toa bipartite NoLS. p8 and, to a lesser extent, p9 repressed viral expression but did not alter Rex-3-dependent mRNA export. Using a transformation assay, we finally showed that none of the STLV-3 auxiliary proteins had the ability to induce colony formation, while both Tax-3 and antisense protein of HTLV-3 (APH-3) promoted cellular transformation. Altogether, these results complete the characterization of the newly described primate T-lymphotropic virus type 3 (PTLV-3). IMPORTANCE: Together with their simian counterparts, HTLVs form the primate T-lymphotropic viruses. HTLVs arose from interspecies transmission between nonhuman primates and humans. HTLV-1 and HTLV-2 encode auxiliary proteins that play important roles in viral replication, viral latency, and immune escape. The presence of ORFs encoding auxiliary proteins in HTLV-3 or STLV-3 genomes wasunknown. Using in silico analyses, ex vivo samples, or in vitro experiments, we have uncovered the presence of 3 previously unknown viral mRNAs encoding putative proteins and confirmed the presence of a previously reported viral transcript. We characterized the intracellular localization of the four proteins. We showed that two of these proteins repress viral expression but that none of them have the ability to induce colony formation. However, both Tax and the antisense protein APH-3 promote cell transformation. Our results allowed us to characterize 4 new retroviral proteins for the first time.

Does transcription play a role in creating a condensin binding site?

Author(s) : Bernard P, Vanoosthuyse V,
Journal : Transcription
The highly conserved condensin complex is essential for the condensation and integrity of chromosomes through cell division. Published data argue that high levels of transcription contribute to specify some condensin-binding sites on chromosomes but the exact role of transcription in this process remains elusive.Here we discuss our recent data addressing the role of transcription in establishing a condensin-binding site.

Effect of replication on epigenetic memory and consequences on gene transcription.

Author(s) : Zerihun M, Vaillant C, Jost D,
Journal : Phys Biol
Gene activity in eukaryotes is in part regulated at the level of chromatin through the assembly of local chromatin states that are more or less permissive to transcription. How do these chromatin states achieve their functions and whether or not they contribute to the epigenetic inheritance of the transcriptional program remain to be elucidated. In cycling cells, stability is indeed strongly challenged by the periodic occurrence of replication and cell division. To address this question, we perform simulations of the stochastic dynamics of chromatin states when driven out-of-equilibrium by periodic perturbations. We show how epigenetic memory is significantly affected by the cell cycle length. In addition, we develop a simple model to connect the epigenetic state to the transcriptional state and gene activity. In particular, it suggests that replication may induce transcriptional bursting at repressive loci. Finally, we discuss how our findings-effect of replication and link to gene transcription-have original and deep implications to various biological contextsof epigenetic memory.

Expression of dengue virus NS3 protein in Drosophila alters its susceptibility to infection.

Author(s) : Querenet M, Danjoy M, Mollereau B, Davoust N,
Journal : Fly (Austin)
We developed a Drosophila model in which the dengue virus NS3 protein is expressed in a tissue specific and inducible manner. Dengue virus NS3 is a multifunctional protein playing a major role during viral replication. Both protease and helicase domains of NS3 are interacting with human and insect host proteins including innate immune components of the host machinery. We characterized the NS3 transgenic flies showing that NS3 expression did not affect fly development. To further study the links between NS3 and the innate immune response, we challenge the flies with gram-positive and gram-negative bacteria. Interestingly, the Drosophila transgenic flies expressing NS3 were more susceptible to bacterial infections than control flies. However ubiquitous or immune-specific NS3 expression affected neither the life span nor the response to a non-infectious stress of the flies. In conclusion, we generated a new in vivo system to study the functional impact of DENV NS3 protein on the innate immune response.

Fatty acid transport proteins in disease: New insights from invertebrate models.

Author(s) : Dourlen P, Sujkowski A, Wessells R, Mollereau B,
Journal : Prog Lipid Res
The dysregulation of lipid metabolism has been implicated in various diseases, including diabetes, cardiopathies, dermopathies, retinal and neurodegenerative diseases. Mouse models have provided insights into lipid metabolism. However, progress in the understanding of these pathologies is hampered by the multiplicity of essential cellular processes and genes that modulate lipid metabolism. Drosophila and Caenorhabditis elegans have emerged as simple geneticmodels to improve our understanding of these metabolic diseases. Recent studies have characterized fatty acid transport protein (fatp) mutants in Drosophila andC. elegans, establishing new models of cardiomyopathy, retinal degeneration, fatstorage disease and dermopathies. These models have generated novel insights into the physiological role of the Fatp protein family in vivo in multicellular organisms, and are likely to contribute substantially to progress in understanding the etiology of various metabolic disorders. Here, we describe anddiscuss the mechanisms underlying invertebrate fatp mutant models in the light of the current knowledge relating to FATPs and lipid disorders in vertebrates.

From Immunodeficiency to Humanization: The Contribution of Mouse Models to Explore HTLV-1 Leukemogenesis.

Author(s) : Peres E, Bagdassarian E, This S, Villaudy J, Rigal D, Gazzolo L, Duc Dodon M,
Journal : Viruses
The first discovered human retrovirus, Human T-Lymphotropic Virus type 1 (HTLV-1), is responsible for an aggressive form of T cell leukemia/lymphoma. Mouse models recapitulating the leukemogenesis process have been helpful for understanding the mechanisms underlying the pathogenesis of this retroviral-induced disease. This review will focus on the recent advances in thegeneration of immunodeficient and human hemato-lymphoid system mice with a particular emphasis on the development of mouse models for HTLV-1-mediated pathogenesis, their present limitations and the challenges yet to be addressed.

Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription.

Author(s) : Marza E, Taouji S, Barroso K, Raymond A, Guignard L, Bonneu M, Pallares-Lupon N, Dupuy J, Fernandez-Zapico M, Rosenbaum J, Palladino F, Dupuy D, Chevet E,
Journal : EMBO Rep
The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPR(ER)) to restore ER homeostasis. TheAAA(+) ATPase p97/CDC-48 plays key roles in ER stress by promoting both ER protein degradation and transcription of UPR(ER) genes. Although the mechanisms associated with protein degradation are now well established, the molecular events involved in the regulation of gene transcription by p97/CDC-48 remain unclear. Using a reporter-based genome-wide RNAi screen in combination with quantitative proteomic analysis in Caenorhabditis elegans, we have identified RUVB-2, a AAA(+) ATPase, as a novel repressor of a subset of UPR(ER) genes. We show that degradation of RUVB-2 by CDC-48 enhances expression of ER stress response genes through an XBP1-dependent mechanism. The functional interplay between CDC-48 and RUVB-2 in controlling transcription of select UPR(ER) genes appears conserved in human cells. Together, these results describe a novel role for p97/CDC-48, whereby its role in protein degradation is integrated with its role in regulating expression of ER stress response genes.

How Retroviruses Escape the Nonsense-Mediated mRNA Decay.

Author(s) : Mocquet V, Durand S, Jalinot P,
Journal : AIDS Res Hum Retroviruses
Many posttranscriptional processes are known to regulate gene expression and some of them can act as an antiviral barrier. The nonsense-mediated mRNA decay (NMD) was first identified as an mRNA quality control pathway that triggers rapid decay of mRNA containing premature stop codons due to mutations. NMD is now consideredas a general posttranscriptional regulation pathway controlling the expression of a large set of cellular genes. In addition to premature stop codons, many other features including alternative splicing, 5' uORF, long 3' UTR, selenocystein codons, and frameshift are able to promote NMD. Interestingly, many viral mRNAs exhibit some of these features suggesting that virus expression and replication might be sensitive to NMD. Several studies, including recent ones, have shown that this is the case for retroviruses; however, it also appears that retroviruses have developed strategies to overcome NMD in order to protect theirgenome and ensure a true expression of their genes. As a consequence of NMD inhibition, these viruses also affect the expression of host genes that are prone to NMD, and therefore can potentially trigger pathological effects on infected cells. Here, we review recent studies supporting this newly uncovered function of the NMD pathway as a defense barrier that viruses must overcome in order to replicate.

In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin.

Author(s) : Laustriat D, Gide J, Barrault L, Chautard E, Benoit C, Auboeuf D, Boland A, Battail C, Artiguenave F, Deleuze J, Benit P, Rustin P, Franc S, Charpentier G, Furling D, Bassez G, Nissan X, Martinat C, Peschanski M, Baghdoyan S,
Journal : Mol Ther Nucleic Acids
Major physiological changes are governed by alternative splicing of RNA, and itsmisregulation may lead to specific diseases. With the use of a genome-wide approach, we show here that this splicing step can be modified by medication anddemonstrate the effects of the biguanide metformin, on alternative splicing. Themechanism of action involves AMPK activation and downregulation of the RBM3 RNA-binding protein. The effects of metformin treatment were tested on myotonic dystrophy type I (DM1), a multisystemic disease considered to be a spliceopathy.We show that this drug promotes a corrective effect on several splicing defects associated with DM1 in derivatives of human embryonic stem cells carrying the causal mutation of DM1 as well as in primary myoblasts derived from patients. The biological effects of metformin were shown to be compatible with typical therapeutic dosages in a clinical investigation involving diabetic patients. Thedrug appears to act as a modifier of alternative splicing of a subset of genes and may therefore have novel therapeutic potential for many more diseases besides those directly linked to defective alternative splicing.

Integrative analysis of RNA, translation, and protein levels reveals distinct regulatory variation across humans.

Author(s) : Cenik C, Cenik E, Byeon G, Grubert F, Candille S, Spacek D, Alsallakh B, Tilgner H, Araya C, Tang H, Ricci E, Snyder M,
Journal : Genome Res
Elucidating the consequences of genetic differences between humans is essential for understanding phenotypic diversity and personalized medicine. Although variation in RNA levels, transcription factor binding, and chromatin have been explored, little is known about global variation in translation and its genetic determinants. We used ribosome profiling, RNA sequencing, and mass spectrometry to perform an integrated analysis in lymphoblastoid cell lines from a diverse group of individuals. We find significant differences in RNA, translation, and protein levels suggesting diverse mechanisms of personalized gene expression control. Combined analysis of RNA expression and ribosome occupancy improves theidentification of individual protein level differences. Finally, we identify genetic differences that specifically modulate ribosome occupancy--many of thesedifferences lie close to start codons and upstream ORFs. Our results reveal a new level of gene expression variation among humans and indicate that genetic variants can cause changes in protein levels through effects on translation.

Photoswitchable Inhibitors of Microtubule Dynamics Optically Control Mitosis and Cell Death.

Author(s) : Borowiak M, Nahaboo W, Reynders M, Nekolla K, Jalinot P, Hasserodt J, Rehberg M, Delattre M, Zahler S, Vollmar A, Trauner D, Thorn-Seshold O,
Journal : Cell
Small molecules that interfere with microtubule dynamics, such as Taxol and the Vinca alkaloids, are widely used in cell biology research and as clinical anticancer drugs. However, their activity cannot be restricted to specific target cells, which also causes severe side effects in chemotherapy. Here, we introducethe photostatins, inhibitors that can be switched on and off in vivo by visible light, to optically control microtubule dynamics. Photostatins modulate microtubule dynamics with a subsecond response time and control mitosis in living organisms with single-cell spatial precision. In longer-term applications in cell culture, photostatins are up to 250 times more cytotoxic when switched on with blue light than when kept in the dark. Therefore, photostatins are both valuabletools for cell biology, and are promising as a new class of precision chemotherapeutics whose toxicity may be spatiotemporally constrained using light.

Predicting pathogen-specific CD8 T cell immune responses from a modeling approach.

Author(s) : Crauste F, Terry E, Mercier I, Mafille J, Djebali S, Andrieu T, Mercier B, Kaneko G, Arpin C, Marvel J, Gandrillon O,
Journal : J Theor Biol
The primary CD8 T cell immune response constitutes a major mechanism to fight aninfection by intra-cellular pathogens. We aim at assessing whether pathogen-specific dynamical parameters of the CD8 T cell response can be identified, based on measurements of CD8 T cell counts, using a modeling approach. We generated experimental data consisting in CD8 T cell counts kinetics during the response to three different live intra-cellular pathogens: two viruses (influenza, vaccinia) injected intranasally, and one bacteria (Listeria monocytogenes) injected intravenously. All pathogens harbor the same antigen (NP68), but differ in their interaction with the host. In parallel, we developeda mathematical model describing the evolution of CD8 T cell counts and pathogen amount during an immune response. This model is characterized by 9 parameters and includes relevant feedback controls. The model outputs were compared with the three data series and an exhaustive estimation of the parameter values was performed. By focusing on the ability of the model to fit experimental data and to produce a CD8 T cell population mainly composed of memory cells at the end ofthe response, critical parameters were identified. We show that a small number of parameters (2-4) define the main features of the CD8 T cell immune response and are characteristic of a given pathogen. Among these parameters, two are related to the effector CD8 T cell mediated control of cell and pathogen death. The parameter associated with memory cell death is shown to play no relevant role during the main phases of the CD8 T cell response, yet it becomes essential whenlooking at the predictions of the model several months after the infection.

RAR/RXR binding dynamics distinguish pluripotency from differentiation associated cis-regulatory elements.

Author(s) : Chatagnon A, Veber P, Morin V, Bedo J, Triqueneaux G, Semon M, Laudet V, d'Alche-Buc F, Benoit G,
Journal : Nucleic Acids Res
In mouse embryonic cells, ligand-activated retinoic acid receptors (RARs) play akey role in inhibiting pluripotency-maintaining genes and activating some major actors of cell differentiation. To investigate the mechanism underlying this dual regulation, we performed joint RAR/RXR ChIP-seq and mRNA-seq time series during the first 48 h of the RA-induced Primitive Endoderm (PrE) differentiation process in F9 embryonal carcinoma (EC) cells. We show here that this dual regulation is associated with RAR/RXR genomic redistribution during the differentiation process. In-depth analysis of RAR/RXR binding sites occupancy dynamics and composition show that in undifferentiated cells, RAR/RXR interact with genomic regions characterized by binding of pluripotency-associated factors and high prevalence of the non-canonical DR0-containing RA response element. By contrast,in differentiated cells, RAR/RXR bound regions are enriched in functional Sox17 binding sites and are characterized with a higher frequency of the canonical DR5motif. Our data offer an unprecedentedly detailed view on the action of RA in triggering pluripotent cell differentiation and demonstrate that RAR/RXR action is mediated via two different sets of regulatory regions tightly associated withcell differentiation status.

Reconstructing and analysing cellular states, space and time from gene expression profiles of many cells and single cells.

Author(s) : Francesconi M, Lehner B,
Journal : Mol Biosyst
Genome-wide gene expression profiling is a fast, cheap and standardised analysisthat provides a high dimensional measurement of the state of a biological sample. In this review we describe computational methods that can be applied to identifyand interpret sources of variance in gene expression in whole organisms, organs,tissues or single cells. This allows the identification of constituent cell types and states in complex mixtures, the reconstruction of temporal trajectories of development, differentiation and progression, and the reconstruction of spatial patterning. When applied to genetically variable samples, these methods allow the efficient investigation of how genetic variation influences gene expression and biological processes in space and time.

Repression of somatic cell fate in the germline.

Author(s) : Robert V, Garvis S, Palladino F,
Journal : Cell Mol Life Sci
Germ cells must transmit genetic information across generations, and produce gametes while also maintaining the potential to form all cell types after fertilization. Preventing the activation of somatic programs is, therefore, crucial to the maintenance of germ cell identity. Studies in Caenorhabditis elegans, Drosophila melanogaster, and mouse have revealed both similarities and differences in how somatic gene expression is repressed in germ cells, thereby preventing their conversion into somatic tissues. This review will focus on recent developments in our understanding of how global or gene-specific transcriptional repression, chromatin regulation, and translational repression operate in the germline to maintain germ cell identity and repress somatic differentiation programs.

Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor.

Author(s) : Gely-Pernot A, Raverdeau M, Teletin M, Vernet N, Feret B, Klopfenstein M, Dennefeld C, Davidson I, Benoit G, Mark M, Ghyselinck N,
Journal : PLoS Genet
All-trans retinoic acid (ATRA) is instrumental to male germ cell differentiation, but its mechanism of action remains elusive. To address this question, we have analyzed the phenotypes of mice lacking, in spermatogonia, all rexinoid receptors (RXRA, RXRB and RXRG) or all ATRA receptors (RARA, RARB and RARG). We demonstrate that the combined ablation of RXRA and RXRB in spermatogonia recapitulates the set of defects observed both upon ablation of RAR in spermatogonia. We also showthat ATRA activates RAR and RXR bound to a conserved regulatory region to increase expression of the SALL4A transcription factor in spermatogonia. Our results reveal that this major pluripotency gene is a target of ATRA signaling and that RAR/RXR heterodimers are the functional units driving its expression inspermatogonia. They add to the mechanisms through which ATRA promote expression of the KIT tyrosine kinase receptor to trigger a critical step in spermatogonia differentiation. Importantly, they indicate also that meiosis eventually occurs in the absence of a RAR/RXR pathway within germ cells and suggest that instructing this process is either ATRA-independent or requires an ATRA signal originating from Sertoli cells.

Scaling, selection, and evolutionary dynamics of the mitotic spindle.

Author(s) : Farhadifar R, Baer C, Valfort A, Andersen E, Muller-Reichert T, Delattre M, Needleman D,
Journal : Curr Biol
BACKGROUND: Cellular structures such as the nucleus, Golgi, centrioles, and spindle show remarkable diversity between species, but the mechanisms that produce these variations in cell biology are not known. RESULTS: Here we investigate the mechanisms that contribute to variations in morphology and dynamics of the mitotic spindle, which orchestrates chromosome segregation in all Eukaryotes and positions the division plane in many organisms. We use high-throughput imaging of the first division in nematodes to demonstrate that the measured effects of spontaneous mutations, combined with stabilizing selection on cell size, are sufficient to quantitatively explain both the levelsof within-species variation in the spindle and its diversity over approximately 100 million years of evolution. Furthermore, our finding of extensive within-species variation for the spindle demonstrates that there is not just one"wild-type" form, rather that cellular structures can exhibit a surprisingly broad diversity of naturally occurring behaviors. CONCLUSIONS: Our results arguethat natural selection acts predominantly on cell size and indirectly influencesthe spindle through the scaling of the spindle with cell size. Previous studies have shown that the spindle also scales with cell size during early development.Thus, the scaling of the spindle with cell size controls its variation over bothontogeny and phylogeny.

Sequential pattern mining for discovering gene interactions and their contextual information from biomedical texts.

Author(s) : Cellier P, Charnois T, Plantevit M, Rigotti C, Cremilleux B, Gandrillon O, Klema J, Manguin J,
Journal : J Biomed Semantics
BACKGROUND: Discovering gene interactions and their characterizations from biological text collections is a crucial issue in bioinformatics. Indeed, text collections are large and it is very difficult for biologists to fully take benefit from this amount of knowledge. Natural Language Processing (NLP) methodshave been applied to extract background knowledge from biomedical texts. Some ofexisting NLP approaches are based on handcrafted rules and thus are time consuming and often devoted to a specific corpus. Machine learning based NLP methods, give good results but generate outcomes that are not really understandable by a user. RESULTS: We take advantage of an hybridization of datamining and natural language processing to propose an original symbolic method toautomatically produce patterns conveying gene interactions and their characterizations. Therefore, our method not only allows gene interactions but also semantics information on the extracted interactions (e.g., modalities, biological contexts, interaction types) to be detected. Only limited resource isrequired: the text collection that is used as a training corpus. Our approach gives results comparable to the results given by state-of-the-art methods and iseven better for the gene interaction detection in AIMed. CONCLUSIONS: Experiments show how our approach enables to discover interactions and their characterizations. To the best of our knowledge, there is few methods that automatically extract the interactions and also associated semantics information. The extracted gene interactions from PubMed are available through a simple web interface at The software is available at

Spen is required for pigment cell survival during pupal development in Drosophila.

Author(s) : Querenet M, Goubard V, Chatelain G, Davoust N, Mollereau B,
Journal : Dev Biol
Apoptosis is required during development to eliminate superfluous cells and sculpt tissues; spatial and timed control of apoptosis ensures that the necessary number of cells is eliminated at a precise time in a given tissue. The elimination of supernumerary pigment or inter-ommatidial cells (IOCs) depends oncell-cell communication and is necessary for the formation of the honeycomb-likestructure of the Drosophila eye. However, the mechanisms occurring during pupal development and controlling apoptosis of superfluous IOC in space and time remain unclear. Here, we found that split-ends (spen) is required for IOC survival at the time of removal of superfluous IOCs. Loss of spen function leads to abnormalremoval of IOCs by apoptosis. We show that spen is required non-autonomously in cone cells for the survival of IOCs by positively regulating the Spitz/EGFR pathway. We propose that Spen is an important survival factor that ensures spatial control of the apoptotic wave that is necessary for the correct patterning and formation of the Drosophila eye.

Temperature-induced variation in gene expression burst size in metazoan cells.

Author(s) : Arnaud O, Meyer S, Vallin E, Beslon G, Gandrillon O,
Journal : BMC Mol Biol
BACKGROUND: Gene expression is an inherently stochastic process, owing to its dynamic molecular nature. Protein amount distributions, which can be acquired bycytometry using a reporter gene, can inform about the mechanisms of the underlying microscopic molecular system. RESULTS: By using different clones of chicken erythroid progenitor cells harboring different integration sites of a CMV-driven mCherry protein, we investigated the dynamical behavior of such distributions. We show that, on short term, clone distributions can be quickly regenerated from small population samples with a high accuracy. On longer term, on the contrary, we show variations manifested by correlated fluctuation in the Mean Fluorescence Intensity. In search for a possible cause of this correlation,we demonstrate that in response to small temperature variations cells are able to adjust their gene expression rate: a modest (2 degrees C) increase in external temperature induces a significant down regulation of mean expression values, with a reverse effect observed when the temperature is decreased. Using a two-state model of gene expression we further demonstrate that temperature acts by modifying the size of transcription bursts, while the burst frequency of the investigated promoter is less systematically affected. CONCLUSIONS: For the first time, we report that transcription burst size is a key parameter for gene expression that metazoan cells from homeotherm animals can modify in response toan external thermal stimulus.

The complex pattern of epigenomic variation between natural yeast strains at single-nucleosome resolution.

Author(s) : Filleton F, Chuffart F, Nagarajan M, Bottin-Duplus H, Yvert G,
Journal : Epigenetics Chromatin
BACKGROUND: Epigenomic studies on humans and model species have revealed substantial inter-individual variation in histone modification profiles. However, the pattern of this variation has not been precisely characterized, particularlyregarding which genomic features are enriched for variability and whether distinct histone marks co-vary synergistically. Yeast allows us to investigate intra-species variation at high resolution while avoiding other sources of variation, such as cell type or subtype. RESULTS: We profiled histone marks H3K4me3, H3K9ac, H3K14ac, H4K12ac and H3K4me1 in three unrelated wild strains ofSaccharomyces cerevisiae at single-nucleosome resolution and analyzed inter-strain differences statistically. All five marks varied significantly at specific loci, but to different extents. The number of nucleosomes varying for agiven mark between two strains ranged from 20 to several thousands; +1 nucleosomes were significantly less subject to variation. Genes with highly evolvable or responsive expression showed higher variability; however, the variation pattern could not be explained by known transcriptional differences between the strains. Synergistic variation of distinct marks was not systematic,with surprising differences between functionally related H3K9ac and H3K14ac. Interestingly, H3K14ac differences that persisted through transient hyperacetylation were supported by H3K4me3 differences, suggesting stabilizationvia cross talk. CONCLUSIONS: Quantitative variation of histone marks among S. cerevisiae strains is abundant and complex. Its relation to functional characteristics is modular and seems modest, with partial association with gene expression divergences, differences between functionally related marks and partial co-variation between marks that may confer stability. Thus, the specificcontext of studies, such as which precise marks, individuals and genomic loci are investigated, is primordial in population epigenomics studies. The complexity found in this pilot survey in yeast suggests that high complexity can be anticipated among higher eukaryotes, including humans.