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  • 1.
    Arnqvist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Novicic, Zorana Kurbalija
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Univ Belgrade, Inst Biol Res Sinisa Stankovic, Despot Stefan Blvd 142, Belgrade 11000, Serbia..
    Castro, Jose A.
    Univ Illes Balears, Fac Ciencies, Dept Biol, Lab Genet, Edifici Guillem Colom,Campus UIB, Palma de Mallorca 07122, Balears, Spain..
    Sayadi, Ahmed
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Negative frequency dependent selection on sympatric mtDNA haplotypes in Drosophila subobscura2016In: Hereditas, ISSN 0018-0661, E-ISSN 1601-5223, Vol. 153, article id 15Article in journal (Refereed)
    Abstract [en]

    Background: Recent experimental evidence for selection on mitochondrial DNA (mtDNA) has prompted the question as to what processes act to maintain within-population variation in mtDNA. Balancing selection though negative frequency dependent selection (NFDS) among sympatric haplotypes is a possibility, but direct empirical evidence for this is very scarce. Findings: We extend the previous findings of a multi-generation replicated cage experiment in Drosophila subobscura, where mtDNA polymorphism was maintained in a laboratory setting. First, we use a set of Monte Carlo simulations to show that the haplotype frequency dynamics observed are inconsistent with genetic drift alone and most closely match those expected under NFDS. Second, we show that haplotype frequency changes over time were significantly different from those expected under either genetic drift or positive selection but were consistent with those expected under NFSD. Conclusions: Collectively, our analyses provide novel support for NFDS on mtDNA haplotypes, suggesting that mtDNA polymorphism may at least in part be maintained by balancing selection also in natural populations. We very briefly discuss the possible mechanisms that might be involved.

  • 2.
    Arnqvist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Sayadi, Ahmed
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Immonen, Elina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Hotzy, Cosima
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Rankin, Daniel
    Univ Zurich, Inst Evolutionary Biol & Environm Studies, Zurich, Switzerland..
    Tuda, Midori
    Kyushu Univ, Dept Bioresource Sci, Lab Insect Nat Enemies, Fukuoka 8128581, Japan.;Kyushu Univ, Inst Biol Control, Fac Agr, Fukuoka 8128581, Japan..
    Hjelmen, Carl E.
    Texas A&M Univ, Dept Entomol, College Stn, TX 77843 USA..
    Johnston, J. Spencer
    Texas A&M Univ, Dept Entomol, College Stn, TX 77843 USA..
    Genome size correlates with reproductive fitness in seed beetles2015In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 282, no 1815, article id 20151421Article in journal (Refereed)
    Abstract [en]

    The ultimate cause of genome size (GS) evolution in eukaryotes remains a major and unresolved puzzle in evolutionary biology. Large-scale comparative studies have failed to find consistent correlations between GS and organismal properties, resulting in the 'C-value paradox'. Current hypotheses for the evolution of GS are based either on the balance between mutational events and drift or on natural selection acting upon standing genetic variation in GS. It is, however, currently very difficult to evaluate the role of selection because within-species studies that relate variation in life-history traits to variation in GS are very rare. Here, we report phylogenetic comparative analyses of GS evolution in seed beetles at two distinct taxonomic scales, which combines replicated estimation of GS with experimental assays of life-history traits and reproductive fitness. GS showed rapid and bidirectional evolution across species, but did not show correlated evolution with any of several indices of the relative importance of genetic drift. Within a single species, GS varied by 4-5% across populations and showed positive correlated evolution with independent estimates of male and female reproductive fitness. Collectively, the phylogenetic pattern of GS diversification across and within species in conjunction with the pattern of correlated evolution between GS and fitness provide novel support for the tenet that natural selection plays a key role in shaping GS evolution.

  • 3. Bard-Chapeau, Emilie A
    et al.
    Nguyen, Anh-Tuan
    Rust, Alistair G
    Sayadi, Ahmed
    Institute of Molecular and Cell Biology, Singapore, Singapore.
    Lee, Philip
    Chua, Belinda Q
    New, Lee-Sun
    de Jong, Johann
    Ward, Jerrold M
    Chin, Christopher K Y
    Chew, Valerie
    Toh, Han Chong
    Abastado, Jean-Pierre
    Benoukraf, Touati
    Soong, Richie
    Bard, Frederic A
    Dupuy, Adam J
    Johnson, Randy L
    Radda, George K
    Chan, Eric Chun Yong
    Wessels, Lodewyk F A
    Adams, David J
    Jenkins, Nancy A
    Copeland, Neal G
    Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model.2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 1Article in journal (Refereed)
    Abstract [en]

    The most common risk factor for developing hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV). To better understand the evolutionary forces driving HCC, we performed a near-saturating transposon mutagenesis screen in a mouse HBV model of HCC. This screen identified 21 candidate early stage drivers and a very large number (2,860) of candidate later stage drivers that were enriched for genes that are mutated, deregulated or functioning in signaling pathways important for human HCC, with a striking 1,199 genes being linked to cellular metabolic processes. Our study provides a comprehensive overview of the genetic landscape of HCC.

  • 4. Bard-Chapeau, Emilie A
    et al.
    Szumska, Dorota
    Jacob, Bindya
    Chua, Belinda Q L
    Chatterjee, Gouri C
    Zhang, Yi
    Ward, Jerrold M
    Urun, Fatma
    Kinameri, Emi
    Vincent, Stéphane D
    Ahmed, Sayadi
    Institute of Molecular and Cell Biology, Singapore, Singapore.
    Bhattacharya, Shoumo
    Osato, Motomi
    Perkins, Archibald S
    Moore, Adrian W
    Jenkins, Nancy A
    Copeland, Neal G
    Mice carrying a hypomorphic Evi1 allele are embryonic viable but exhibit severe congenital heart defects2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2Article in journal (Refereed)
    Abstract [en]

    The ecotropic viral integration site 1 (Evi1) oncogenic transcription factor is one of a number of alternative transcripts encoded by the Mds1 and Evi1 complex locus (Mecom). Overexpression of Evi1 has been observed in a number of myeloid disorders and is associated with poor patient survival. It is also amplified and/or overexpressed in many epithelial cancers including nasopharyngeal carcinoma, ovarian carcinoma, ependymomas, and lung and colorectal cancers. Two murine knockout models have also demonstrated Evi1's critical role in the maintenance of hematopoietic stem cell renewal with its absence resulting in the death of mutant embryos due to hematopoietic failure. Here we characterize a novel mouse model (designated Evi1(fl3)) in which Evi1 exon 3, which carries the ATG start, is flanked by loxP sites. Unexpectedly, we found that germline deletion of exon3 produces a hypomorphic allele due to the use of an alternative ATG start site located in exon 4, resulting in a minor Evi1 N-terminal truncation and a block in expression of the Mds1-Evi1 fusion transcript. Evi1(δex3/δex3) mutant embryos showed only a mild non-lethal hematopoietic phenotype and bone marrow failure was only observed in adult Vav-iCre/+, Evi1(fl3/fl3) mice in which exon 3 was specifically deleted in the hematopoietic system. Evi1(δex3/δex3) knockout pups are born in normal numbers but die during the perinatal period from congenital heart defects. Database searches identified 143 genes with similar mutant heart phenotypes as those observed in Evi1(δex3/δex3) mutant pups. Interestingly, 42 of these congenital heart defect genes contain known Evi1-binding sites, and expression of 18 of these genes are also effected by Evi1 siRNA knockdown. These results show a potential functional involvement of Evi1 target genes in heart development and indicate that Evi1 is part of a transcriptional program that regulates cardiac development in addition to the development of blood.

  • 5.
    Bayram, Helen L.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Sayadi, Ahmed
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Uppsala Univ, Dept Ecol & Genet, Evolutionary Biol Ctr, Norbyvagen 18D, SE-75236 Uppsala, Sweden..
    Goenaga, Julieta
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Aarhus Univ, Aarhus Inst Adv Studies, Aarhus, Denmark..
    Immonen, Elina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Arnqvist, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Novel seminal fluid proteins in the seed beetle Callosobruchus maculatus identified by a proteomic and transcriptomic approach2017In: Insect molecular biology (Print), ISSN 0962-1075, E-ISSN 1365-2583, Vol. 26, no 1, p. 58-73Article in journal (Refereed)
    Abstract [en]

    The seed beetle Callosobruchus maculatus is a significant agricultural pest and increasingly studied model of sexual conflict. Males possess genital spines that increase the transfer of seminal fluid proteins (SFPs) into the female body. As SFPs alter female behaviour and physiology, they are likely to modulate reproduction and sexual conflict in this species. Here, we identified SFPs using proteomics combined with a de novo transcriptome. A prior 2D-sodium dodecyl sulphate polyacrylamide gel electrophoresis analysis identified male accessory gland protein spots that were probably transferred to the female at mating. Proteomic analysis of these spots identified 98 proteins, a majority of which were also present within ejaculates collected from females. Standard annotation workflows revealed common functional groups for SFPs, including proteases and metabolic proteins. Transcriptomic analysis found 84 transcripts differentially expressed between the sexes. Notably, genes encoding 15 proteins were highly expressed in male abdomens and only negligibly expressed within females. Most of these sequences corresponded to 'unknown' proteins (nine of 15) and may represent rapidly evolving SFPs novel to seed beetles. Our combined analyses highlight 44 proteins for which there is strong evidence that they are SFPs. These results can inform further investigation, to better understand the molecular mechanisms of sexual conflict in seed beetles.

  • 6. Dudgeon, Crissy
    et al.
    Shreeram, Sathyavageeswaran
    Tanoue, Kan
    Mazur, Sharlyn J
    Sayadi, Ahmed
    Institute of Molecular and Cell Biology; Proteos; Singapore.
    Robinson, Robert C
    Appella, Ettore
    Bulavin, Dmitry V
    Genetic variants and mutations of PPM1D control the response to DNA damage2013In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 12, no 16Article in journal (Refereed)
    Abstract [en]

    The Wip1 phosphatase is an oncogene that is overexpressed in a variety of primary human cancers. We were interested in identifying genetic variants that could change Wip1 activity. We identified 3 missense SNPs of the human Wip1 phosphatase, L120F, P322Q, and I496V confer a dominant-negative phenotype. On the other hand, in primary human cancers, PPM1D mutations commonly result in a gain-of-function phenotype, leading us to identify a hot-spot truncating mutation at position 525. Surprisingly, we also found a significant number of loss-of-function mutations of PPM1D in primary human cancers, both in the phosphatase domain and in the C terminus. Thus, PPM1D has evolved to generate genetic variants with lower activity, potentially providing a better fitness for the organism through suppression of multiple diseases. In cancer, however, the situation is more complex, and the presence of both activating and inhibiting mutations requires further investigation to understand their contribution to tumorigenesis.

  • 7. Gould, Cathryn M
    et al.
    Diella, Francesca
    Via, Allegra
    Puntervoll, Pål
    Gemünd, Christine
    Chabanis-Davidson, Sophie
    Michael, Sushama
    Sayadi, Ahmed
    Department of Biochemical Sciences, ‘Sapienza Universita’ di Roma, Rome, Italy.
    Bryne, Jan Christian
    Chica, Claudia
    Seiler, Markus
    Davey, Norman E
    Haslam, Niall
    Weatheritt, Robert J
    Budd, Aidan
    Hughes, Tim
    Pas, Jakub
    Rychlewski, Leszek
    Travé, Gilles
    Aasland, Rein
    Helmer-Citterich, Manuela
    Linding, Rune
    Gibson, Toby J
    ELM: the status of the 2010 eukaryotic linear motif resource.2010In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 38Article in journal (Refereed)
    Abstract [en]

    Linear motifs are short segments of multidomain proteins that provide regulatory functions independently of protein tertiary structure. Much of intracellular signalling passes through protein modifications at linear motifs. Many thousands of linear motif instances, most notably phosphorylation sites, have now been reported. Although clearly very abundant, linear motifs are difficult to predict de novo in protein sequences due to the difficulty of obtaining robust statistical assessments. The ELM resource at http://elm.eu.org/ provides an expanding knowledge base, currently covering 146 known motifs, with annotation that includes >1300 experimentally reported instances. ELM is also an exploratory tool for suggesting new candidates of known linear motifs in proteins of interest. Information about protein domains, protein structure and native disorder, cellular and taxonomic contexts is used to reduce or deprecate false positive matches. Results are graphically displayed in a 'Bar Code' format, which also displays known instances from homologous proteins through a novel 'Instance Mapper' protocol based on PHI-BLAST. ELM server output provides links to the ELM annotation as well as to a number of remote resources. Using the links, researchers can explore the motifs, proteins, complex structures and associated literature to evaluate whether candidate motifs might be worth experimental investigation.

  • 8.
    Immonen, Elina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Sayadi, Ahmed
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Bayram, Helen
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Arnqvist, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Mating Changes Sexually Dimorphic Gene Expression in the Seed Beetle Callosobruchus maculatus2017In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 9, no 3, p. 677-699Article in journal (Refereed)
    Abstract [en]

    Sexually dimorphic phenotypes arise largely from sex-specific gene expression, which hasmainly been characterized in sexually naive adults. However, we expect sexual dimorphism in transcription to be dynamic and dependent on factors such as reproductive status. Mating induces many behavioral and physiological changes distinct to each sex and is therefore expected to activate regulatory changes in many sex-biased genes. Here, we first characterized sexual dimorphism in gene expression in Callosobruchus maculatus seed beetles. We then examined how females and males respond to mating and how it affects sex-biased expression, both in sex-limited (abdomen) and sex-shared (head and thorax) tissues. Mating responses were largely sex-specific and, as expected, females showed more genes responding compared with males (similar to 2,000 vs. similar to 300 genes in the abdomen, similar to 500 vs. similar to 400 in the head and thorax, respectively). Of the sex-biased genes present in virgins, 16%(1,041 genes) in the abdomen and 17%(243 genes) in the head and thorax altered their relative expression between the sexes as a result of mating. Sex-bias status changed in 2% of the genes in the abdomen and 4% in the head and thorax following mating. Mating responses involved de-feminization of females and, to a lesser extent, de-masculinization of males relative to their virgin state: mating decreased rather than increased dimorphic expression of sex-biased genes. The fact that regulatory changes of both types of sex-biased genes occurred in both sexes suggests that male-and female-specific selection is not restricted to male-and female-biased genes, respectively, as is sometimes assumed.

  • 9. Lalle, Marco
    et al.
    Camerini, Serena
    Cecchetti, Serena
    Sayadi, Ahmed
    Department of Biochemical Sciences, University of Rome “Sapienza”, Rome, Italy.
    Crescenzi, Marco
    Pozio, Edoardo
    Interaction network of the 14-3-3 protein in the ancient protozoan parasite Giardia duodenalis.2012In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 11, no 5, p. 2666-2683Article in journal (Refereed)
    Abstract [en]

    14-3-3s are phosphoserine/phosphotreonine binding proteins that play pivotal roles as regulators of multiple cellular processes in eukaryotes. The flagellated protozoan parasite Giardia duodenalis, the causing agent of giardiasis, is a valuable simplified eukaryotic model. A single 14-3-3 isoform (g14-3-3) is expressed in Giardia, and it is directly involved in the differentiation of the parasite into cyst. To define the overall functions of g14-3-3, the protein interactome has been investigated. A transgenic G. duodenalis strain was engineered to express a FLAG-tagged g14-3-3 under its own promoter. Affinity chromatography coupled with tandem mass spectrometry analysis have been used to purify and identify FLAG-g14-3-3-associated proteins from trophozoites and encysting parasites. A total of 314 putative g14-3-3 interaction partners were identified, including proteins involved in several pathways. Some interactions seemed to be peculiar of one specific stage, while others were shared among the different stages. Furthermore, the interaction of g14-3-3 with the giardial homologue of the CDC7 protein kinase (gCDC7) was characterized, leading to the identification of a multiprotein complex containing not only g14-3-3 and gCDC7 but also a newly identified and highly divergent homologue of DBF4, the putative regulatory subunit of gCDC7. The relevance of g14-3-3 interactions in G. duodenalis biology was discussed.

  • 10.
    Sayadi, Ahmed
    et al.
    Department of Physics, Sapienza University of Rome, Rome, Italy.
    Briganti, Leonardo
    Department of Biology, University of Rome ‘‘Tor Vergata’’, Rome, Italy.
    Tramontano, Anna
    Department of Physics, Sapienza University of Rome, Rome, Italy, Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
    Via, Allegra
    Department of Physics, Sapienza University of Rome, Rome, Italy.
    Exploiting Publicly Available Biological and Biochemical Information for the Discovery of Novel Short Linear Motifs2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203Article in journal (Refereed)
  • 11.
    Sayadi, Ahmed
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Immonen, Elina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arnqvist, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    The Evolution of Dark Matter in the Mitogenome of Seed Beetles2017In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 9, no 10, p. 2697-2706Article in journal (Refereed)
    Abstract [en]

    Animal mitogenomes are generally thought of as being economic and optimized for rapid replication and transcription. We use long-read sequencing technology to assemble the remarkable mitogenomes of four species of seed beetles. These are the largest circular mitogenomes ever assembled in insects, ranging from 24,496 to 26,613 bp in total length, and are exceptional in that some 40% consists of non-coding DNA. The size expansion is due to two very long intergenic spacers (LIGSs), rich in tandem repeats. The two LIGSs are present in all species but vary greatly in length (114-10,408 bp), show very low sequence similarity, divergent tandem repeat motifs, a very high AT content and concerted length evolution. The LIGSs have been retained for at least some 45 my but must have undergone repeated reductions and expansions, despite strong purifying selection on protein coding mtDNA genes. The LIGSs are located in two intergenic sites where a few recent studies of insects have also reported shorter LIGSs (>200 bp). These sites may represent spaces that tolerate neutral repeat array expansions or, alternatively, the LIGSs may function to allow a more economic translational machinery. Mitochondrial respiration in adult seed beetles is based almost exclusively on fatty acids, which reduces the need for building complex I of the oxidative phosphorylation pathway (NADH dehydrogenase). One possibility is thus that the LIGSs may allow depressed transcription of NAD genes. RNA sequencing showed that LIGSs are partly transcribed and transcriptional profiling suggested that all seven mtDNA NAD genes indeed show low levels of transcription and co-regulation of transcription across sexes and tissues.

  • 12.
    Sayadi, Ahmed
    et al.
    Institute of Molecular and Cell Biology, Singapore, Singapore.
    Jeyakani, J
    Seet, S H
    Wei, C-L
    Bourque, G
    Bard, F A
    Jenkins, N A
    Copeland, N G
    Bard-Chapeau, E A
    Functional features of EVI1 and EVI1Δ324 isoforms of MECOM gene in genome-wide transcription regulation and oncogenicity.2015In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594Article in journal (Refereed)
    Abstract [en]

    The MDS1 and ecotropic viral integration site 1 (EVI1) complex locus (MECOM) gene encodes several transcription factor variants including MDS1-EVI1, EVI1 and EVI1Δ324. Although MDS1-EVI1 has been associated with tumor-suppressing activity, EVI1 is a known oncogene in various cancers, whose expression is associated with poor patient survival. Although EVI1Δ324 is co-transcribed with EVI1, its activity in cancer cells is not fully understood. Previous reports described that unlike EVI1, EVI1Δ324 protein cannot transform fibroblasts because of its disrupted N-terminal zinc finger (ZNF) domain. To better understand EVI1Δ324 biology and function, we obtained genome-wide binding occupancies and expression data in ovarian cancer cells. We characterized its DNA-binding sites, binding motif and target genes. Comparative analyses with previous study show that EVI1 and EVI1Δ324 share similar transcriptional activities linked to their common C-terminus ZNF domain. They bind to an E-twenty-six family (ETS)-like motif, target to a large extent the same genes and cooperate with AP1 transcription factor. EVI1Δ324-occupied genes were 70.7% similar to EVI1-bound genes. More strikingly, EVI1 and EVI1Δ324 differentially expressed genes were 99.87% identical, indicating comparable transcriptional regulatory functions. Consistently with gene ontologies linked to these target genes, EVI1Δ324 expression in HeLa cells could enhance anchorage-independent growth, such as EVI1, showing that EVI1Δ324 expression also lead to pro-oncogenic effects. The main specific feature of EVI1 variant is its N-terminus ZNF domain that binds DNA through GATA-like motif. We found that most GATA-like EVI1 chromatin immunoprecipitation sequencing peaks are far from genes and are not involved in transcriptional regulation. These genomic regions were enriched in simple sequence repeats and displayed high meiotic recombination rates. Overall, our genomics analyses uncovered common and specific features of two major MECOM isoforms. Their influence on transcription and downstream cell proliferation was comparable. However, EVI1-specific GATA-like binding sites, from its N-terminus ZNF domain, associated with high recombination rates, suggesting possible additional oncogenic potential for EVI1 in modulating genomic stability.Oncogene advance online publication, 3 August 2015; doi:10.1038/onc.2015.286.

  • 13.
    Sayadi, Ahmed
    et al.
    Institute Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
    Nguyen, Anh-Tuan
    Institute Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
    Bard, Frederic A
    Institute Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
    Bard-Chapeau, Emilie A
    Institute Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
    Zip14 expression induced by lipopolysaccharides in macrophages attenuates inflammatory response2013In: Inflammation Research, ISSN 1023-3830, E-ISSN 1420-908X, Vol. 62, no 2Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE AND DESIGN: We investigated the role and regulation of zinc transporters in the activation of the inflammatory response in macrophages. Our exploratory computational study found that Zip14 (SLC39A14) was consistently up-regulated in activated macrophages; we therefore focused subsequently on that gene in the mechanistic study.

    MATERIAL: The expression and function of Zip14 was assessed in primary macrophages obtained by in-vitro differentiation of monocytes from human blood.

    METHODS: Primary macrophages were subjected to treatments with lipopolysaccharides, cytokines, chemicals, and pharmacological agents. SLC39A14 and inflammatory cytokine gene expressions were assessed by RT-qPCR. Zip14 siRNA knockdown was performed to explore the gene function.

    RESULTS: Lipopolysaccharide's inflammatory stimulus was a strong inducer of SLC39A14 mRNA expression in macrophages. This induction was dependent on calcium signaling, GC-rich DNA-binding, and NF-κB down-regulation. Impregnation of lipopolysaccharide-stimulated macrophages with the glucocorticoid dexamethasone further enhanced Zip14 expression while reducing interleukin-6 and tumor necrosis factor-α production. Zip14 knockdown in macrophages attenuated the expression and secretion of cytokines, indicating a buffering function for this zinc transporter.

    CONCLUSIONS: Collectively, our results identified the zinc transporter Zip14 as expressed downstream of lipopolysaccharide signals in macrophages. Zip14 induction had a regulatory function in cytokine production.

  • 14.
    Stojkovic, Biljana
    et al.
    Univ Belgrade, Inst Zool, Fac Biol, Studentski Trg 16, Belgrade 11000, Serbia.;Univ Belgrade, Inst Biol Res Sinisa Stankovic, Dept Evolutionary Biol, Despota Stefana Blvd 142, Belgrade 11060, Serbia..
    Sayadi, Ahmed
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Dordevic, Mirko
    Univ Belgrade, Inst Biol Res Sinisa Stankovic, Dept Evolutionary Biol, Despota Stefana Blvd 142, Belgrade 11060, Serbia..
    Jovic, Jelena
    Inst Plant Protect & Environm, Dept Plant Pests, Banatska 33, Zemun 11080, Serbia..
    Savkovic, Uros
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Arnqvist, Göran
    Univ Belgrade, Inst Biol Res Sinisa Stankovic, Dept Evolutionary Biol, Despota Stefana Blvd 142, Belgrade 11060, Serbia..
    Divergent evolution of life span associated with mitochondrial DNA evolution2017In: Evolution, ISSN 0014-3820, E-ISSN 1558-5646, Vol. 71, no 1, p. 160-166Article in journal (Refereed)
    Abstract [en]

    Mitochondria play a key role in ageing. The pursuit of genes that regulate variation in life span and ageing have shown that several nuclear-encoded mitochondrial genes are important. However, the role of mitochondrial encoded genes (mtDNA) is more controversial and our appreciation of the role of mtDNA for the evolution of life span is limited. We use replicated lines of seed beetles that have been artificially selected for long or short life for >190 generations, now showing dramatic phenotypic differences, to test for a possible role of mtDNA in the divergent evolution of ageing and life span. We show that these divergent selection regimes led to the evolution of significantly different mtDNA haplotype frequencies. Selection for a long life and late reproduction generated positive selection for one specific haplotype, which was fixed in most such lines. In contrast, selection for reproduction early in life led to both positive selection as well as negative frequency-dependent selection on two different haplotypes, which were both present in all such lines. Our findings suggest that the evolution of life span was in part mediated by mtDNA, providing support for the emerging general tenet that adaptive evolution of life-history syndromes may involve mtDNA.

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