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  • 51.
    Senti, Gabriele
    et al.
    Södertörn University, School of Life Sciences.
    Ezcurra, Marina
    Löbner, Jana
    Södertörn University, School of Life Sciences.
    Schafer, William R.
    Swoboda, Peter
    Södertörn University, School of Life Sciences, Molecular biology.
    Worms With a Single Functional Sensory Cilium Generate Proper Neuron-Specific Behavioral Output2009In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 183, no 2, p. 595-605Article in journal (Refereed)
    Abstract [en]

    Studying the development and mechanisms of sensory perception is challenging in organisms with complex neuronal networks. The worm Caenorhabditis elegans possesses a simple neuronal network of 302 neurons that includes 60 ciliated sensory neurons (CSNs) for detecting external sensory input. C. elegans is thus an excellent model in which to study sensory neuron development., function, and behavior. We have generated a genetic rescue system that allows in vivo analyses of isolated CSNs at both cellular and systemic levels. We used the RFX transcription factor DAF-19, a key regulator of ciliogenesis. Mutations in daf-19 result in the complete absence of all sensory cilia and thus of external sensory input. In daf-19 mutants, we used cell-specific rescue of DAF-19 function in selected neurons, thereby generating animals with single, fully functional CSNs. Otherwise and elsewhere these animals are completely devoid of any environmental input through cilia. We demonstrated the rescue of fully functional, single cilia using fluorescent markers, sensory behavioral assays, and calcium imaging. Our technique, functional rescue in single sensory cilia (FRISSC), can thus cell-autonomously and cell-specifically restore the function of single sensory neurons and their ability to respond to sensory input. FRISSC can be adapted to many different CSNs and thus constitutes an excellent tool for studying sensory behaviors, both in single animals and in populations of worms. FRISSC will be Very useful for the molecular dissection of sensory perception in CSNs and for the analysis of the developmental aspects of ciliogenesis.

  • 52.
    Shiue, Chiounan N
    et al.
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Berkson, Rachel G.
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Wright, Anthony P H
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    c-Myc induces changes in higher order rDNA structure on stimulation of quiescent cells2009In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 28, no 16, p. 1833-1842Article in journal (Refereed)
    Abstract [en]

    c-Myc is an oncogenic transcription factor capable of activating transcription by all three nuclear RNA polymerases, thus acting as a high-level coordinator of protein synthesis capacity and cell growth rate. c-Myc recruits RNA polymerase I-related transcription factors to the rDNA when quiescent cells are stimulated to re-enter the cell cycle. Using a model system of cell lines with variable c-Myc status, we show that on stimulation c-Myc rapidly induces gene loop structures in rDNA chromatin that juxtapose upstream and downstream rDNA sequences. c-Myc activation is both necessary and sufficient for this change in rDNA chromatin conformation. c-Myc activation induces association of TTF-1 with the rDNA, and c-Myc is physically associated with induced rDNA gene loops. The origins of two or more rDNA gene loops are closely juxtaposed, suggesting the possibility that c-Myc induces nucleolar chromatin hubs. Induction of rDNA gene loops may be an early step in the reprogramming of quiescent cells as they re-enter the growth cycle.

  • 53.
    Sinha, Indranil
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Intstitutet.
    Genome-wide patterns of histone modifications in fission yeast2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    DNA is wrapped almost two times around a group of proteins called histones to form a chromosomal structure known as the nucleosome. Both DNA and histones can be modified with different chemical tags by several enzymes to activate or suppress a particular gene or group of genes. Histones can be covalently modified at several places. Among many different types of post-translational histone modifications, histone acetylation and methylation are two important modification types that are associated with transcriptional activation and repression. Histone acetylation and methylation can be added by histone acetyltransferases (HATs) and histone methyletransferases (HMTs), whereas these modifications can be removed by histone deacetylases (HDACs) and histone demethylases (HDMs). Histone modifications are not only involved in the regulation of gene expression, but also in DNA-based processes, such as replication, repair, and the formation and maintenance of heterochromatin. Combinations of modified and unmodified states of histones can form distinct histone modification patterns. In many different genome-wide studies, it was observed that a distinctive pattern of histone modification in various organisms is important for gene regulation, DNA replication, chromosome segregation and heterochromatin-mediated silencing. In this thesis, we have conducted several genome-wide investigations to uncover different histone modification patterns and their roles in transcriptional control in fission yeast. Our analysis of six different HDACs in fission yeast showed that Clr6 and Clr3 are mainly involved in keeping repressed genes silent; Sir2 and Hst2 repress non-expressed genes, and Hst4 acts globally to reduce gene expression, whereas Hos2 is required for the activation of gene expression. By investigating the influence of each HDAC on nucleosome density, we found that all sirtuins and Hos2 enzymes are required to maintain normal nucleosome density and distribution in the S. pombe genome. We have reported that histone acetylation patterns show a 5` to 3` polarity, i.e., the modification levels peak near the ATG and gradually decrease in the coding regions. We also found that histone acetylation patterns depend on gene expression but are independent of gene length. Comparing our data with other published datasets, we observed that different HDAC mutants affect acetylation in different parts of open reading frames (ORFs). We have demonstrated that histone H4 acetylation proceeds in the direction from K16 to K5, consistent with a `zip` model that may be involved in transcriptional control. Our analysis revealed antagonistic crosstalk between H3K36me2/me3 and H3K27ac at promoter regions. We observed that histone H3 K18, K27 and K9 acetylation positively correlate with gene expression, and a conserved pattern was also reported in other organisms. Finally, we report that histone H4K20me1 is strongly linked to active genes, whereas H4K20me3 is associated with weakly expressed genes. Our analysis further shows that H4K20me1 modification levels peak at 3‟UTR regions in active genes. Thus, our analysis revealed many different aspects of histone modification patterns and their roles in transcriptional control in fission yeast.

  • 54.
    Sinha, Indranil
    et al.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Buchanan, Luke
    Technische Universität Dresden, Dresden, Germany / Max Planck Institute, Dresten, Germany.
    Rönnerblad, Michelle
    Karolinska Institutet.
    Bonilla, Carolina
    Karolinska Institutet.
    Durand-Dubief, Mickael
    Karolinska Institutet.
    Shevchenko, Andrej
    Max Planck Institute, Dresten, Germany.
    Grunstein, Michael
    Geffen School of Medicine at UCLA, & the Molecular Biology Institute, Los Angeles, USA.
    Stewart, A. Francis
    Technische Universität Dresden, Dresden, Germany.
    Ekwall, Karl
    Karolinska Institutet.
    Genome-wide mapping of histone modifications and mass spectrometry reveal H4 acetylation bias and H3K36 methylation at gene promoters in fission yeast2010In: Epigenomics, ISSN 1750-1911, Vol. 2, no 3, p. 377-393Article in journal (Refereed)
    Abstract [en]

    To map histone modifications with unprecedented resolution both globally and locus-specifically, and to link modification patterns to gene expression. Materials & methods: Using correlations between quantitative mass spectrometry and chromatin immunoprecipitation/microarray analyses, we have mapped histone post-translational modifications in fission yeast (Schizosaccharomyces pombe). Results: Acetylations at lysine 9, 18 and 27 of histone H3 give the best positive correlations with gene expression in this organism. Using clustering analysis and gene ontology search tools, we identified promoter histone modification patterns that characterize several classes of gene function. For example, gene promoters of genes involved in cytokinesis have high H3K36me2 and low H3K4me2, whereas the converse pattern is found ar promoters of gene involved in positive regulation of the cell cycle. We detected acetylation of H4 preferentially at lysine 16 followed by lysine 12, 8 and 5. Our analysis shows that this H4 acetylation bias in the coding regions is dependent upon gene length and linked to gene expression. Our analysis also reveals a role for H3K36 methylation at gene promoters where it functions in a crosstalk between the histone methyltransferase Set2(KMT3) and the histone deacetylase Clr6, which removes H3K27ac leading to repression of transcription. Conclusion: Histone modification patterns could be linked to gene expression in fission yeast.

  • 55.
    Sinha, Indranil
    et al.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Jemt, Elisabeth
    Göteborgs universitet.
    Durand-Dubief, Mickaël
    Baraham Institute, Cambridge, UK.
    Stålfors, Annelie
    Karolinska Institutet.
    Sanders, Steven
    Case Western Reserve university, Cleveland, USA.
    Ekwall, Karl
    Karolinska Institutet.
    Gnome wide mapping suggests different roles for H4K20me1 and H4K20me3 in gene expressionManuscript (preprint) (Other academic)
  • 56. Stenvall, Jörgen
    et al.
    Fierro-Gonzalez, Juan Carlos
    Södertörn University, School of Life Sciences, Molecular biology.
    Swoboda, Peter
    Södertörn University, School of Life Sciences, Molecular biology.
    Saamarthy, Karunakar
    Cheng, Qing
    Cacho-Valadez, Briseida
    Arner, Elias S. J.
    Persson, Olof P.
    Miranda-Vizuete, Antonio
    Tuck, Simon
    Selenoprotein TRXR-1 and GSR-1 are essential for removal of old cuticle during molting in Caenorhabditis elegans2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 3, p. 1064-1069Article in journal (Refereed)
    Abstract [en]

    Selenoproteins, in particular thioredoxin reductase, have been implicated in countering oxidative damage occurring during aging but the molecular functions of these proteins have not been extensively investigated in different animal models. Here we demonstrate that TRXR-1 thioredoxin reductase, the sole selenoprotein in Caenorhabditis elegans, does not protect against acute oxidative stress but functions instead together with GSR-1 glutathione reductase to promote the removal of old cuticle during molting. We show that the oxidation state of disulfide groups in the cuticle is tightly regulated during the molting cycle, and that when trxr-1 and gsr-1 function is reduced, disulfide groups in the cuticle remain oxidized. A selenocysteine-to-cysteine TRXR-1 mutant fails to rescue molting defects. Furthermore, worms lacking SELB-1, the C. elegans homolog of Escherichia coli SelB or mammalian EFsec, a translation elongation factor known to be specific for selenocysteine in E. coli, fail to incorporate selenocysteine, and display the same phenotype as those lacking trxr-1. Thus, TRXR-1 function in the reduction of old cuticle is strictly selenocysteine dependent in the nematode. Exogenously supplied reduced glutathione reduces disulfide groups in the cuticle and induces apolysis, the separation of old and new cuticle, strongly suggesting that molting involves the regulated reduction of cuticle components driven by TRXR-1 and GSR-1. Using dauer larvae, we demonstrate that aged worms have a decreased capacity to molt, and decreased expression of GSR-1. Together, our results establish a function for the selenoprotein TRXR-1 and GSR-1 in the removal of old cuticle from the surface of epidermal cells.

  • 57. Strålfors, Annelie
    et al.
    Walfridsson, Julian
    Södertörn University, School of Life Sciences, Molecular biology.
    Bhuiyan, Hasanuzzaman
    Södertörn University, School of Life Sciences, Molecular biology.
    Ekwall, Karl
    Södertörn University, School of Life Sciences, Molecular biology.
    The FUN30 Chromatin Remodeler, Fft3, Protects Centromeric and Subtelomeric Domains from Euchromatin Formation2011In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 7, no 3, article id e1001334Article in journal (Refereed)
    Abstract [en]

    The chromosomes of eukaryotes are organized into structurally and functionally discrete domains. This implies the presence of insulator elements that separate adjacent domains, allowing them to maintain different chromatin structures. We show that the Fun30 chromatin remodeler, Fft3, is essential for maintaining a proper chromatin structure at centromeres and subtelomeres. Fft3 is localized to insulator elements and inhibits euchromatin assembly in silent chromatin domains. In its absence, euchromatic histone modifications and histone variants invade centromeres and subtelomeres, causing a mis-regulation of gene expression and severe chromosome segregation defects. Our data strongly suggest that Fft3 controls the identity of chromatin domains by protecting these regions from euchromatin assembly.

  • 58.
    Tong, Yong-Guang
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Intsitutet.
    Regulatory function of homeobox genes in the development of Caenorhabditis elegans2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The nematode worm Caenorhabditis elegans has been widely used as a genetic model for over 40 years to investigate developmental control genes. In this thesis, I studied the roles of several homeobox genes and a novel RNA binding protein (RBD) in the development of C. elegans to understand the function of these genes in higher organisms. Homeobox genes are transcriptional regulators that are highly conserved in evolution and play important domains in eukaryotes, and genes encoding this domain play roles in a wide variety of post-transcriptional gene regulation processes. In paper I, we characterized a novel protein, RNA binding domain-1 (RBD-1), which is involved in ribosome biogenesis. This protein contains six consensus RNA-binding domains and is conserved as to sequence, domain organization, and subcellular localization from yeast to human. RBD-1 is essential for the development of C. elegans. The RNAi experiments using the cDNA of RBD-1 demonstrated various abnormalities in the C. elegans development, such as defects in morphology (dumpy), incomplete molting, and defective gonadal and vulval development. Animals depleted for RBD-1 arrested mainly at the L1 larval stage. In the course of studying the homeobox genes, we often used the dye-filling assay. It is the simplest method presently used to assay the structural integrity of sensory cilia. In paper II, we optimized conditions, in which reliable staining of the inner labial (IL2) neurons could be obtained, namely in low salt conditions, in the presence of determethod to distinguish mutant alleles that stain amphids and phasmids, and IL2 neurons. Using this assay, we found that a mutation in the POU homeobox gene unc-86 abolished dye-filling in IL2 neurons but not amphids and phasmids. mids. In Paper III, we showed that the LIM homeobox gene ceh-14 was expressed in other sensory neurons and interneurons, including the phasmid neurons and the ALA interneuron, while previously it was shown that ceh-14 is expressed in the AFD neurons and required for thermotaxis behavior in C. elegans. ceh-14 mutant animals displayed defects in dendrite outgrowth of the phasmid neurons, while the ALA interneuron and some tail neurons showed ceh-14 and the paired-like homeobox gene ceh-17 act in the separate pathway to control normal axonal outgrowth of ALA neuron. Overexpression of CEH-14 in the nervous system may titrate out interacting factors, such as LDB-1, which caused developmental defects In paper IV, we investigated the function of four homeobox genes, ceh-6, ceh-26, ttx-1 and ceh-37, in the excretory cell development. We showed that the POU-III class homeobox gene ceh-6, the Prospero class homeobox gene ceh-26, and two otd/Otx family homeobox genes, ceh-37 and ttx-1 formed a regulatory hierarchy required for the development and function of the excretory cell in C. elegans. The excretory cell is required for maintaining osmotic balance and excreting waste products. While ceh-6 has previously been demonstrated to play a role in the excretory cell patterning, we showed here that ceh-26 and ceh-37 are expressed in the excretory cell. ceh-26 mutants arrested in early larval development with defects characteristic for a lack of excretory cell function. Double mutant of the otd/Otx genes ceh-37 and ttx-1 was displaying larval arrest, consistent with the excretory cell dysfunction, which indicates that there is functional redundancy between these two genes. Using mutant alleles and RNAi, we showed that ceh-26::GFP and ceh-37::GFP was down-regulated in ceh-6 mutants. Further, we found that ceh-37::GFP was down-regulated in the ceh-26 genes, such as channel proteins (the target genes ) that are expressed in the excretory cell and found that only a subset of the genes regulated by ceh-6 was also regulated by ceh-37/ttx-1. We mapped the promoter regions of ceh-26 and of the target gene clh-4 to identify putative homeodomain proteins binding sites. Given that these homeobox genes are well conserved in evolution, we may expect that parts of this cascade are also conserved in other organisms.

  • 59.
    Tong, Yong-Guang
    et al.
    Södertörn University, School of Life Sciences, Molecular biology.
    Bürglin, Thomas R.
    Södertörn University, School of Life Sciences, Molecular biology.
    Conditions for dye-filling of sensory neurons in Caenorhabditis elegans2010In: Journal of Neuroscience Methods, ISSN 0165-0270, E-ISSN 1872-678X, Vol. 188, no 1, p. 58-61Article in journal (Refereed)
    Abstract [en]

    Dye-filling is a common method used to stain Caenorhabditis elegans ensory neurons in vivo. While the amphids and phasmids are easy to tain, a subset of sensory neurons, the IL2 neurons, are difficult to tain reproducibly. Here we examined the conditions under which the IL2 eurons take up the lipophilic fluorescent dye DiI. We find that IL2 ye-filling depends on salt concentration, but not osmolarity. Low salt rior and during incubation is important for efficient dye uptake. dditional parameters that affect dye-filling are the speed of shaking uring incubation and the addition of detergents. Our modified ye-filling procedure provides a reliable method to distinguish mutant lleles that stain amphids and phasmids, IL2 neurons, or both. An dditional benefit is that it can also stain the excretory duct. The ethod allows genetic screens to be performed to identify mutants that electively affect only one of the sensory structures or the excretory uct.

  • 60.
    Tong, Yong-Guang
    et al.
    Södertörn University, School of Life Sciences, Molecular biology.
    Meenon, K.
    Meenon, K.
    Prétôt, R.
    Viktorin-Aspöck, G.
    Bürglin, Thomas R.
    Södertörn University, School of Life Sciences, Molecular biology.
    A regulatory network of homeobox genes is required for the function of the Caenorhabditis elegans excretory cellManuscript (preprint) (Other academic)
  • 61. Vladic, Tomislav
    et al.
    Forsberg, Lars A.
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Järvi, Torbjörn
    Sperm competition between alternative reproductive tactics of the Atlantic salmon in vitro2010In: Aquaculture, ISSN 0044-8486, E-ISSN 1873-5622, Vol. 302, no 04-mar, p. 265-269Article in journal (Refereed)
    Abstract [en]

    The maintenance of brood stock in appropriate conditions is an important equirement for the production of high quality offspring. In this study, e investigated fertility of the two life history forms of Atlantic almon males, precocious parr, brought up in breeding tanks in the atchery and anadromous, migratory searanched males, caught when eturning to the home river. The sperm quality was assessed by xperiments between equal amount of sperm from one adult and one parr ale in competition to fertilize eggs of a single female. The paternity as determined by a microsatellite analysis. Parr males achieved greater eproductive success than anadromous males under competition, and nadromous adults had greater fertility in controls as compared to the perm competition situation. In total, parr males achieved 3.6 times reater fertilization success than anadromous males. Sperm ATP content ontributed significantly to male fertility. Our results provide vidence that ejaculates of precociously mature Atlantic salmon parr are f increased quality as an adaptation to high sperm competition ntensity due to better maintenance in the fish farm than in the wild.

  • 62.
    Volkova, Kristina
    et al.
    Södertörn University, School of Life Sciences, Environmental science.
    Reyhanian, Nasim
    Södertörn University, School of Life Sciences, Environmental science. Södertörn University, School of Life Sciences, Molecular biology.
    Kot-Wasik, Agata
    Gdańsk University of Technology.
    Olsén, Håkan
    Södertörn University, School of Life Sciences, Environmental science. Södertörn University, School of Life Sciences, Biology.
    Porsch-Hällström, Inger
    Södertörn University, School of Life Sciences, Environmental science. Södertörn University, School of Life Sciences, Molecular biology.
    Hallgren, Stefan
    Södertörn University, School of Life Sciences, Environmental science. Södertörn University, School of Life Sciences, Biology.
    Brain circuit imprints of developmental 17α-ethinylestradiol exposure in guppies (Poecilia reticulata): Persistent effects on anxiety but not on reproductive behaviour2012In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 178, no 2, p. 282-290Article in journal (Refereed)
    Abstract [en]

    The effects of endocrine disruptors may vary with the timing of exposure. The physiological implications of adult exposure are present during and shortly after exposure while embryonic exposure can imprint changes manifested in adulthood. In this study, guppy (Poecilia reticulata) embryos were exposed to 2 ng/L and 20 ng/L of 17α-ethinylestradiol during development via the mother and reared in clean water from gestation until 6 months of age. As adults, fish exposed to 20ng/L during development showed significantly altered behaviour in the Novel Tank test, where anxiety is determined as the tendency to remain at the bottom upon introduction into an unfamiliar tank. 17α-ethinylestradiol treatment increased the latency time before swimming to the upper half of the tank and decreased the number of transitions to the upper half. In control females the basal stress behaviour responses were significantly higher than in males, as indicated by longer latency period and fewer and shorter visits to the upper half, supporting the importance of gonadal hormones for the behaviour. The anxiety increased, however, with treatment in both sexes, suggesting that the observed response is not entirely due to feminization of the males. Shoaling behaviour, analyzed as tendency to leave a shoal of littermates, was neither sex-differentiated nor changed by treatment. Also male reproductive behaviour, brain aromatase activity and testes histology, previously shown to respond to oestrogen exposure in adult guppy, were unaffected by the developmental treatment. This suggests that the stress system in the guppy is very sensitive to 17α-ethinylestradiol, which possibly causes an early organisational imprint on the brain circuit that regulates stress reactions.

  • 63.
    Wigerius, Michael
    Södertörn University, School of Life Sciences, Chemistry. Södertörn University, School of Life Sciences, Molecular biology.
    Roles of mammalian Scribble in polarity signaling, virus offense and cell-fate determination2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mammalian Scribble is a target for proteins encoded by human papilloma virus, retro- and flaviviruses. Tick-borne encephalitis virus (TBEV) is a flavivirus that have evolved distinct strategies to escape antiviral responses. Information of how flaviviruses intrude on cell integrity comes from understanding of the roles that host-factors play when they interfere with viruses. The first part of this thesis describes a novel interaction between the TBEVNS5 protein and Scribble. The importance of the interaction was demonstrated by RNAi-mediated depletion of Scribble, which prevented suppression of JAK-STAT signaling by NS5. Together, these results define Scribble as a novel target for NS5.

    TBEV is known to cause central nervous system disease TBE in humans that can lead to cognitive dysfunction. A unifying theme in CNS related diseases are defects in neuronal extensions. We therefore addressed the effects of TBEV expression in PC12 cell differentiation, which is characterized by extensive neurite growth. Our data show that TBEVNS5 suppresses neurite outgrowth through the Rho GTPase Rac1. These findings provide evidence that Rac1 is an indirect target of NS5 in neurite inhibition. Scribble was recently implicated in spine morphogenesis. Thus, we tested the role of Scribble in neurite elongation. Depletion of Scribble in PC12 cells, reduced neurite density but increased length of those remaining. Moreover, Scribble bound components in the Ras/ERK cascade in a growth factor dependent manner. Together, these results demonstrate that Scribble controls neurite elongation by scaffolding MAPK components. Moreover, as loss of dendritic spines, actin-rich protrusions on neurons, is a feature in cognitive dysfunction we speculate that cognitive dysfunction in TBE might involve disturbed Scribble expression by NS5.

    We also investigated the binding between NS1 of Influenza A virus and Scribble. The PDZ domains of Scribble are usually selective for specific C-terminal motifs in proteins. Because NS1 has a canonical PDZ motif we tested if binding to Scribble depends on this motif. We found that Scribble binds NS1; the association is dependent on the NS1 C-terminus that is recognized by PDZ3-4 of Scribble. Together, these results suggest that Scribble is a target for the H5N1 NS1 protein 

  • 64.
    Wigerius, Michael
    et al.
    Södertörn University, School of Life Sciences, Molecular biology. Södertörn University, School of Life Sciences, Chemistry.
    Johansson, Magnus
    Södertörn University, School of Life Sciences, International health. Södertörn University, School of Life Sciences, Chemistry.
    SCRIBBLE SCAFFOLDS KEY COMPONENTS IN NEURITE OUTGROWTHIMPLICATING DIRECT INVOLVEMENT IN CYTOSKELETON REGULATIONManuscript (preprint) (Other academic)
  • 65.
    Wigerius, Michael
    et al.
    Södertörn University, School of Life Sciences, Chemistry. Södertörn University, School of Life Sciences, Molecular biology.
    Melik, Wessam
    Södertörn University, School of Life Sciences, Chemistry. Södertörn University, School of Life Sciences, Molecular biology.
    Elväng, Annelie
    Södertörn University, School of Life Sciences, Molecular biology.
    Johansson, Magnus
    Södertörn University, School of Life Sciences, Chemistry. Södertörn University, School of Life Sciences, International health.
    Rac1 and Scribble are targets for the arrest of neurite outgrowth by TBE virus NS52010In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 44, no 3, p. 260-271Article in journal (Refereed)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) causes extensive CNS disease in humans known as TBE, however, relatively little is known of the molecular mechanisms for its progress. Here, we now show that TBEV produces defects in neuronal development of PC12 cells through a function of the viral NS5 protein. The methyltransferase domain of NS5 is critical and sufficient for restriction of nerve growth factor induced neurite outgrowth. This effect is reversed by expression of NS5 mutants unable to bind Scribble and unexpectedly, in Scribble depleted cells with binding-competent NS5. Furthermore, we also demonstrate that the Rho GTPase Rac1 and the guanine nucleotide-exchange factor, beta PIX are outcompeted by NS5 for binding to Scribble, linking to effects on neurite outgrowth by TBEV. Together, these findings provide the first experimental evidence that Rac1 and beta PIX are indirect targets of NS5 acting through the multifunctional polarity protein Scribble to oppose neuronal differentiation. In conclusion, our results offer a potential mechanism by which TBEV alters neuronal circuitry and opens new avenues for therapeutic interventions.

  • 66. Wrzaczek, Michael
    et al.
    Brosche, Mikael
    Salojarvi, Jarkko
    Kangasjarvi, Saijaliisa
    Idanheimo, Niina
    Mersmann, Sophia
    Robatzek, Silke
    Karpinski, Stanislaw
    Karpinska, Barbara
    Södertörn University, School of Life Sciences, Biology. Södertörn University, School of Life Sciences, Molecular biology.
    Kangasjarvi, Jaakko
    Transcriptional regulation of the CRK/DUF26 group of Receptor-like rotein kinases by ozone and plant hormones in Arabidopsis2010In: BMC Plant Biology, ISSN 1471-2229, E-ISSN 1471-2229, Vol. 10, p. 95-Article in journal (Refereed)
    Abstract [en]

    Background: Plant Receptor-like/Pelle kinases (RLK) are a group of onserved signalling components that regulate developmental programs and esponses to biotic and abiotic stresses. One of the largest RLK groups s formed by the Domain of Unknown Function 26 (DUF26) RLKs, also called ysteine-rich Receptor-like Kinases (CRKs), which have been suggested to lay important roles in the regulation of pathogen defence and rogrammed cell death. Despite the vast number of RLKs present in lants, however, only a few of them have been functionally haracterized. esults: We examined the transcriptional regulation of all Arabidopsis RKs by ozone (O(3)), high light and pathogen/ elicitor reatment-conditions known to induce the production of reactive oxygen pecies (ROS) in various subcellular compartments. Several CRKs were ranscriptionally induced by exposure to O(3) but not by light stress. (3) induces an extracellular oxidative burst, whilst light stress leads o ROS production in chloroplasts. Analysis of publicly available icroarray data revealed that the transcriptional responses of the CRKs o O(3) were very similar to responses to microbes or athogen-associated molecular patterns (PAMPs). Several mutants altered n hormone biosynthesis or signalling showed changes in basal and (3)-induced transcriptional responses. onclusions: Combining expression analysis from multiple treatments with utants altered in hormone biosynthesis or signalling suggest a model in hich O(3) and salicylic acid (SA) activate separate signaling pathways hat exhibit negative crosstalk. Although O(3) is classified as an biotic stress to plants, transcriptional profiling of CRKs showed trong similarities between the O(3) and biotic stress responses.

  • 67.
    Xue-Franzen, Yongtao
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Intitutet.
    DNA microarray approaches to understanding the regulation and evolution of gene expression networks2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    DNA microarray technology allows biological and medical research to shift from investigation of individual functions of a few related genes to the whole genome level. This creates opportunities for discovery of complex and coordinated transcriptional networks in biological systems. The aim of this thesis has been to study gene regulation and evolution using yeast responses to environmental cues as a model system. We first developed and validated a fission yeast cDNA microarray for genome-wide expression analysis (Paper I). It is the first commercially available fission yeast microarray, which presents a useful resouce for yeast researchers and provides information required to contruct the array from scratch. Next, we characterised the gene regulatory networks involved in the pheromone response (Paper II) and investigate the role of Gcn5 transcription co-regulator, a histone acetyltransferase (HAT), in re-programming gene expression during the salt stress response in fission yeast (Paper III). We further investigated evolutionary conservation and divergence of Gcn5 in gene regulation by comparing its role in the evolutionarily distantly related yeast species. The parallel study of the fission yeast and budding yeast showed that Gcn5 has a conserved physiological role in salt stress responses, but it regulates diverged sets of stress response genes potentially via distinct mechanisms (paper IV). Finally, we investigated interactions between different HATs and between HATs and HDACs (histone deacetylases). Phenotypic studies and gene expression profiling revealed that Gcn5 has overlapping functions with another HAT, Mst2, in the stress response and DNA damage repair (Paper V). We found that the HDAC Clr3 acts antagonistically to Gcn5 in transcriptional elongation and stress responses (Paper VI).

  • 68.
    Xue-Franzen, Yongtao
    et al.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Johnsson, Anna
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Intitutet.
    Brodin, David
    Karolinska Institutet.
    Henriksson, Johan
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Bürglin, Thomas R.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Wright, Anthony P. H.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Genome-wide characterisation of the Gcn5 histone acetyltransferase in budding yeast during stress adaptation reveals evolutionarily conserved and diverged roles2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, article id 200Article in journal (Refereed)
    Abstract [en]

    Background: Gcn5 is a transcriptional coactivator with histone cetyltransferase activity that is conserved with regard to structure as ell as its histone substrates throughout the eukaryotes. Gene egulatory networks within cells are thought to be evolutionarily iverged. The use of evolutionarily divergent yeast species, such as S. erevisiae and S. pombe, which can be studied under similar nvironmental conditions, provides an opportunity to examine the nterface between conserved regulatory components and their cellular pplications in different organisms. esults: We show that Gcn5 is important for a common set of stress esponses in evolutionarily diverged yeast species and that the activity f the conserved histone acetyltransferase domain is required. We define group of KCl stress response genes in S. cerevisiae that are pecifically dependent on Gcn5. Gcn5 is localised to many Gcn5-dependent enes including Gcn5 repressed targets such as FLO8. Gcn5 regulates ivergent sets of KCl responsive genes in S. cerevisiae and S. pombe. enome-wide localization studies showed a tendency for redistribution of cn5 during KCl stress adaptation in S. cerevisiae from short genes to he transcribed regions of long genes. An analogous redistribution was ot observed in S. pombe. onclusions: Gcn5 is required for the regulation of divergent sets of Cl stress-response genes in S. cerevisiae and S. pombe even though it s required a common group of stress responses, including the response o KCl. Genes that are physically associated with Gcn5 require its ctivity for their repression or activation during stress adaptation, roviding support for a role of Gcn5 as a corepressor as well as a oactivator. The tendency of Gcn5 to re-localise to the transcribed egions of long genes during KCl stress adaptation suggests that Gcn5 lays a specific role in the expression of long genes under adaptive onditions, perhaps by regulating transcriptional elongation as has been een for Gcn5 in S. pombe. Interestingly an analogous redistribution of cn5 is not seen in S. pombe. The study thus provides important new nsights in relation to why coregulators like Gcn5 are required for the orrect expression of some genes but not others.

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