@article{YanChenSchumacheretal.2019, author = {Yan, Wenhao and Chen, Dijun and Schumacher, Julia and Durantini, Diego and Engelhorn, Julia and Chen, Ming and Carles, Cristel C. and Kaufmann, Kerstin}, title = {Dynamic control of enhancer activity drives stage-specific gene expression during flower morphogenesis}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, publisher = {Nature Publ. Group}, address = {London}, issn = {2041-1723}, doi = {10.1038/s41467-019-09513-2}, pages = {16}, year = {2019}, abstract = {Enhancers are critical for developmental stage-specific gene expression, but their dynamic regulation in plants remains poorly understood. Here we compare genome-wide localization of H3K27ac, chromatin accessibility and transcriptomic changes during flower development in Arabidopsis. H3K27ac prevalently marks promoter-proximal regions, suggesting that H3K27ac is not a hallmark for enhancers in Arabidopsis. We provide computational and experimental evidence to confirm that distal DNase. hypersensitive sites are predictive of enhancers. The predicted enhancers are highly stage-specific across flower development, significantly associated with SNPs for flowering-related phenotypes, and conserved across crucifer species. Through the integration of genome-wide transcription factor (TF) binding datasets, we find that floral master regulators and stage-specific TFs are largely enriched at developmentally dynamic enhancers. Finally, we show that enhancer clusters and intronic enhancers significantly associate with stage-specific gene regulation by floral master TFs. Our study provides insights into the functional flexibility of enhancers during plant development, as well as hints to annotate plant enhancers.}, language = {en} } @misc{CorstenGuentherNieslonyetal.2016, author = {Corsten, Sabine and G{\"u}nther, Thomas and Nieslony, Julia and Fl{\"o}ther, Manfred and Rott, Anke and Sch{\"o}ppe, Doreen and K{\"o}sterke-Buchardt, Antje and Machleb, Franziska and Purat, Patricia and Euler, Harald A. and Breitenstein, Sarah and D{\"u}sterh{\"o}ft, Stefanie and Posse, Dorothea and Topaj, Nathalie and Golcher, Felix and Gagarina, Natalʹja Vladimirovna and Stegenwallner-Sch{\"u}tz, Maja Henny Katherine and Lassotta, Romy and Ferchland, Lisa and Adani, Flavia and Wotschack, Christiane and Klassert, Annegret and Festman, Julia and Schumacher, Rebecca and Burchert, Frank and Ablinger, Irene and Buttler, Rahel and Frank, Luis and Stadie, Nicole and Weiland, Linda and Netzebandt, Jonka and Frank, Ulrike and Bykova, Ksenia and Loppnow, Anna and Huckabee, Maggie-Lee and Krusche, Lisa}, title = {Spektrum Patholinguistik Band 9. Schwerpunktthema: Lauter Laute: Phonologische Verarbeitung und Lautwahrnehmung in der Sprachtherapie}, series = {Spektrum Patholinguistik}, journal = {Spektrum Patholinguistik}, editor = {Fritzsche, Tom and Yetim, {\"O}zlem and Otto, Constanze and Adelt, Anne}, publisher = {Universit{\"a}tsverlag Potsdam}, address = {Potsdam}, isbn = {978-3-86956-385-5}, issn = {1866-9085}, doi = {10.25932/publishup-9665}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-96653}, pages = {vi, 269}, year = {2016}, abstract = {Das 9. Herbsttreffen Patholinguistik mit dem Schwerpunktthema "Lauter Laute: Phonologische Verarbeitung und Lautwahrnehmung in der Sprachtherapie" fand am 14.11.2015 in Potsdam statt. Das Herbsttreffen wird seit 2007 j{\"a}hrlich vom Verband f{\"u}r Patholinguistik e.V. (vpl) durchgef{\"u}hrt. Der vorliegende Tagungsband beinhaltet die vier Hauptvortr{\"a}ge zum Schwerpunktthema, die drei Kurzvortr{\"a}ge aus dem Spektrum Patholinguisitk sowie die Beitr{\"a}ge der Posterpr{\"a}sentationen zu weiteren Themen aus der sprachtherapeutischen Forschung und Praxis.}, language = {de} } @phdthesis{Schumacher2019, author = {Schumacher, Julia}, title = {Regulation and function of STERILE APETALA in Arabidopsis flower development}, school = {Universit{\"a}t Potsdam}, pages = {144}, year = {2019}, abstract = {STERILE APETALA (SAP) is known to be an essential regulator of flower development for over 20 years. Loss of SAP function in the model plant Arabidopsis thaliana is associated with a reduction of floral organ number, size and fertility. In accordance with the function of SAP during early flower development, its spatial expression in flowers is confined to meristematic stages and to developing ovules. However, to date, despite extensive research, the molecular function of SAP and the regulation of its spatio-temporal expression still remain elusive. In this work, amino acid sequence analysis and homology modeling revealed that SAP belongs to the rare class of plant F-box proteins with C-terminal WD40 repeats. In opisthokonts, this type of F-box proteins constitutes the substrate binding subunit of SCF complexes, which catalyze the ubiquitination of proteins to initiate their proteasomal degradation. With LC-MS/MS-based protein complex isolation, the interaction of SAP with major SCF complex subunits was confirmed. Additionally, candidate substrate proteins, such as the growth repressor PEAPOD 1 and 2 (PPD1/2), could be revealed during early stages of flower development. Also INDOLE-3-BUTYRIC ACID RESPONSE 5 (IBR5) was identified among putative interactors. Genetic analyses indicated that, different from substrate proteins, IBR5 is required for SAP function. Protein complex isolation together with transcriptome profiling emphasized that the SCFSAP complex integrates multiple biological processes, such as proliferative growth, vascular development, hormonal signaling and reproduction. Phenotypic analysis of sap mutant and SAP overexpressing plants positively correlated SAP function with plant growth during reproductive and vegetative development. Furthermore, to elaborate on the transcriptional regulation of SAP, publicly available ChIP-seq data of key floral homeotic proteins were reanalyzed. Here, it was shown that the MADS-domain transcription factors APETALA 1 (AP1), APETALA 3 (AP3), PISTILLATA (PI), AGAMOUS (AG) and SEPALLATA 3 (SEP3) bind to the SAP locus, which indicates that SAP is expressed in a floral organ-specific manner. Reporter gene analyses in combination with CRISPR/Cas9-mediated deletion of putative regulatory regions further demonstrated that the intron contains major regulatory elements of SAP in Arabidopsis thaliana. In conclusion, these data indicate that SAP is a pleiotropic developmental regulator that acts through tissue-specific destabilization of proteins. The presumed transcriptional regulation of SAP by the floral MADS-domain transcription factors could provide a missing link between the specification of floral organ identity and floral organ growth pathways.}, language = {en} } @article{MeinersPalmieriKlopfleischetal.2019, author = {Meiners, Jana and Palmieri, Vittoria and Klopfleisch, Robert and Ebel, Jana-Fabienne and Japtok, Lukasz and Schumacher, Fabian and Yusuf, Ayan Mohamud and Becker, Katrin Anne and Z{\"o}ller, Julia and Hose, Matthias and Kleuser, Burkhard and Hermann, Dirk Matthias and Kolesnick, Richard N. and Buer, Jan and Hansen, Wiebke and Westendorf, Astrid M.}, title = {Intestinal acid sphingomyelinase protects from severe Pathogen-Driven Colitis}, series = {Frontiers in immunology}, volume = {10}, journal = {Frontiers in immunology}, publisher = {Frontiers Research Foundation}, address = {Lausanne}, issn = {1664-3224}, doi = {10.3389/fimmu.2019.01386}, pages = {14}, year = {2019}, abstract = {Inflammatory diseases of the gastrointestinal tract are emerging as a global problem with increased evidence and prevalence in numerous countries. A dysregulated sphingolipid metabolism occurs in patients with ulcerative colitis and is discussed to contribute to its pathogenesis. In the present study, we determined the impact of acid sphingomyelinase (Asm), which catalyzes the hydrolysis of sphingomyelin to ceramide, on the course of Citrobacter (C.) rodentium-driven colitis. C. rodentium is an enteric pathogen and induces colonic inflammation very similar to the pathology in patients with ulcerative colitis. We found that mice with Asm deficiency or Asm inhibition were strongly susceptible to C. rodentium infection. These mice showed increased levels of C. rodentium in the feces and were prone to bacterial spreading to the systemic organs. In addition, mice lacking Asm activity showed an uncontrolled inflammatory T(h)1 and T(h)17 response, which was accompanied by a stronger colonic pathology compared to infected wild type mice. These findings identified Asm as an essential regulator of mucosal immunity to the enteric pathogen C. rodentium.}, language = {en} } @article{HausmannZoschkeWolffetal.2019, author = {Hausmann, Christian and Zoschke, Christian and Wolff, Christopher and Darvin, Maxim E. and Sochorova, Michaela and Kovacik, Andrej and Wanjiku, Barbara and Schumacher, Fabian and Tigges, Julia and Kleuser, Burkhard and Lademann, Juergen and Fritsche, Ellen and Vavrova, Katerina and Ma, Nan and Schaefer-Korting, Monika}, title = {Fibroblast origin shapes tissue homeostasis, epidermal differentiation, and drug uptake}, series = {Scientific reports}, volume = {9}, journal = {Scientific reports}, publisher = {Nature Publ. Group}, address = {London}, issn = {2045-2322}, doi = {10.1038/s41598-019-39770-6}, pages = {10}, year = {2019}, abstract = {Preclinical studies frequently lack predictive value for human conditions. Human cell-based disease models that reflect patient heterogeneity may reduce the high failure rates of preclinical research. Herein, we investigated the impact of primary cell age and body region on skin homeostasis, epidermal differentiation, and drug uptake. Fibroblasts derived from the breast skin of female 20- to 30-yearolds or 60- to 70-year-olds and fibroblasts from juvenile foreskin (<10 years old) were compared in cell monolayers and in reconstructed human skin (RHS). RHS containing aged fibroblasts differed from its juvenile and adult counterparts, especially in terms of the dermal extracellular matrix composition and interleukin-6 levels. The site from which the fibroblasts were derived appeared to alter fibroblast-keratinocyte crosstalk by affecting, among other things, the levels of granulocyte-macrophage colony-stimulating factor. Consequently, the epidermal expression of filaggrin and e-cadherin was increased in RHS containing breast skin fibroblasts, as were lipid levels in the stratum corneum. In conclusion, the region of the body from which fibroblasts are derived appears to affect the epidermal differentiation of RHS, while the age of the fibroblast donors determines the expression of proteins involved in wound healing. Emulating patient heterogeneity in preclinical studies might improve the treatment of age-related skin conditions.}, language = {en} } @article{ChakrabortyChenBornhorstetal.2015, author = {Chakraborty, Sudipta and Chen, Pan and Bornhorst, Julia and Schwerdtle, Tanja and Schumacher, Fabian and Kleuser, Burkhard and Bowman, Aaron B. and Aschner, Michael A.}, title = {Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C-elegans}, series = {Metallomics : integrated biometal science}, volume = {7}, journal = {Metallomics : integrated biometal science}, number = {5}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {1756-5901}, doi = {10.1039/c5mt00052a}, pages = {847 -- 856}, year = {2015}, language = {en} } @article{SchumacherChakrabortyKleuseretal.2015, author = {Schumacher, Fabian and Chakraborty, Sudipta and Kleuser, Burkhard and Gulbins, Erich and Schwerdtle, Tanja and Aschner, Michael A. and Bornhorst, Julia}, title = {Highly sensitive isotope-dilution liquid-chromatography-electrospray ionization-tandem-mass spectrometry approach to study the drug-mediated modulation of dopamine and serotonin levels in Caenorhabditis elegans}, series = {Talanta : the international journal of pure and applied analytical chemistry}, volume = {144}, journal = {Talanta : the international journal of pure and applied analytical chemistry}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0039-9140}, doi = {10.1016/j.talanta.2015.05.057}, pages = {71 -- 79}, year = {2015}, abstract = {Dopamine (DA) and serotonin (SRT) are monoamine neurotransmitters that play a key role in regulating the central and peripheral nervous system. Their impaired metabolism has been implicated in several neurological disorders, such as Parkinson's disease and depression. Consequently, it is imperative to monitor changes in levels of these low-abundant neurotransmitters and their role in mediating disease. For the first time, a rapid, specific and sensitive isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of DA and SRT in the nematode Caenorhabditis elegans (C. elegans). This model organism offers a unique approach for studying the effect of various drugs and environmental conditions on neurotransmitter levels, given by the conserved DA and SRT biology, including synaptic release, trafficking and formation. We introduce a novel sample preparation protocol incorporating the usage of sodium thiosulfate in perchloric acid as extraction medium that assures high recovery of the relatively unstable neurotransmitters monitored. Moreover, the use of both deuterated internal standards and the multiple reaction monitoring (MRM) technique allows for unequivocal quantification. Thereby, to the best of our knowledge, we achieve a detection sensitivity that clearly exceeds those of published DA and SRT quantification methods in various matrices. We are the first to show that exposure of C elegans to the monoamine oxidase B (MAOB) inhibitor selegiline or the catechol-O-methyltransferase (COMT) inhibitor tolcapone, in order to block DA and SRT degradation, resulted in accumulation of the respective neurotransmitter. Assessment of a behavioral output of the dopaminergic system (basal slowing response) corroborated the analytical LC-MS/MS data. Thus, utilization of the C elegans model system in conjunction with our analytical method is well-suited to investigate drug-mediated modulation of the DA and SRT system in order to identify compounds with neuroprotective or regenerative properties. (C) 2015 Elsevier B.V. All rights reserved.}, language = {en} } @misc{ChakrabortyChenBornhorstetal.2015, author = {Chakraborty, Sudipta and Chen, Pan and Bornhorst, Julia and Schwerdtle, Tanja and Schumacher, Fabian and Kleuser, Burkhard and Bowman, Aaron B. and Aschner, Michael A.}, title = {Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-99508}, pages = {10}, year = {2015}, abstract = {Overexposure to the essential metal manganese (Mn) can result in an irreversible condition known as manganism that shares similar pathophysiology with Parkinson's disease (PD), including dopaminergic (DAergic) cell loss that leads to motor and cognitive impairments. However, the mechanisms behind this neurotoxicity and its relationship with PD remain unclear. Many genes confer risk for autosomal recessive, early-onset PD, including the parkin/PARK2 gene that encodes for the E3 ubiquitin ligase Parkin. Using Caenorhabditis elegans (C. elegans) as an invertebrate model that conserves the DAergic system, we previously reported significantly increased Mn accumulation in pdr-1/parkin mutants compared to wildtype (WT) animals. For the current study, we hypothesize that this enhanced accumulation is due to alterations in Mn transport in the pdr-1 mutants. While no change in mRNA expression of the major Mn importer proteins (smf-1-3) was found in pdr-1 mutants, significant downregulation in mRNA levels of the putative Mn exporter ferroportin (fpn-1.1) was observed. Using a strain overexpressing fpn-1.1 in worms lacking pdr-1, we show evidence for attenuation of several endpoints of Mn-induced toxicity, including survival, metal accumulation, mitochondrial copy number and DAergic integrity, compared to pdr-1 mutants alone. These changes suggest a novel role of pdr-1 in modulating Mn export through altered transporter expression, and provides further support of metal dyshomeostasis as a component of Parkinsonism pathophysiology.}, language = {en} }