Publications

@article{nokey,

title = {Unlocking the Full Potential of Nanopore Sequencing: Tips, Tricks, and Advanced Data Analysis Techniques},

author = {Daria Meyer and Winfried Göttsch and Jannes Spangenberg and Bettina Stieber and Sebastian Krautwurst and Martin Hoelzer and Christian Brandt and Joerg Linde and Christian {Höner zu Siederdissen} and Akash Srivastava and Milena Zarkovic and Damian Wollny and Manja Marz},

doi = {10.1101/2023.12.06.570356},

year  = {2025},

date = {2025-01-27},

urldate = {2025-01-27},

journal = {bioRxiv},

abstract = {Nucleic acid sequencing is the process of identifying the sequence of DNA or RNA, with DNA used for genomes and RNA for transcriptomes. Deciphering this information has the potential to greatly advance our understanding of genomic features and cellular functions. In comparison to other available sequencing methods, nanopore sequencing stands out due to its unique advantages of processing long nucleic acid strands in real time, within a small portable device, enabling the rapid analysis of samples in diverse settings. Evolving over the past decade, nanopore sequencing remains in a state of ongoing development and refinement, resulting in persistent challenges in protocols and technology. This article employs an interdisciplinary approach, evaluating experimental and computational methods to address critical gaps in our understanding in order to maximize the information gain from this advancing technology. Here we present both overview and analysis of all aspects of nanopore sequencing by providing statistically supported insights. Thus, we aim to provide fresh perspectives on nanopore sequencing and give comprehensive guidelines for the diverse challenges that frequently impede optimal experimental outcomes.},

keywords = {differential expression analysis, DNA / genomics, nanopore, nucleic acid modifications},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Comprehensive transcriptome analysis reveals altered mRNA splicing and post-transcriptional changes in the aged mouse brain},

author = {Nisha Hemandhar Kumar and Verena Kluever and Emanuel Barth and Sebastian Krautwurst and Mattia Furlan and Mattia Pelizzola and Manja Marz and Eugenio F Fornasiero},

doi = {10.1093/nar/gkae172},

year  = {2024},

date = {2024-04-12},

urldate = {2024-04-12},

journal = {Nucleic Acids Research},

volume = {52},

abstract = {A comprehensive understanding of molecular changes during brain aging is essential to mitigate cognitive decline and delay neurodegenerative diseases. The interpretation of mRNA alterations during brain aging is influenced by the health and age of the animal cohorts studied. Here, we carefully consider these factors and provide an in-depth investigation of mRNA splicing and dynamics in the aging mouse brain, combining short- and long-read sequencing technologies with extensive bioinformatic analyses. Our findings encompass a spectrum of age-related changes, including differences in isoform usage, decreased mRNA dynamics and a module showing increased expression of neuronal genes. Notably, our results indicate a reduced abundance of mRNA isoforms leading to nonsense-mediated RNA decay and suggest a regulatory role for RNA-binding proteins, indicating that their regulation may be altered leading to the reshaping of the aged brain transcriptome. Collectively, our study highlights the importance of studying mRNA splicing events during brain aging.},

keywords = {differential expression analysis, RNA / transcriptomics, splicing},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Differential Transcriptional Responses of Human Granulocytes to Fungal Infection with \textit{Candida albicans} and \textit{Aspergillus fumigatus}},

author = {Tilman E. Klassert and Martin Hölzer and Cristina Zubiria-Barrera and Julia Bethge and Esther Klaile and Mario M. Müller and Manja Marz and Hortense Slevogt},

doi = {doi.org/10.3390/jof9101014},

year  = {2023},

date = {2023-10-14},

journal = {J Fungi},

volume = {9},

issue = {10},

pages = {1014},

abstract = {Neutrophils are critical phagocytic cells in innate immunity, playing a significant role in defending against invasive fungal pathogens. This study aimed to explore the transcriptional activation of human neutrophils in response to different fungal pathogens, including Candida albicans and Aspergillus fumigatus, compared to the bacterial pathogen Escherichia coli. We identified distinct transcriptional profiles and stress-related pathways in neutrophils during fungal infections, highlighting their functional diversity and adaptability. The transcriptional response was largely redundant across all pathogens in immune-relevant categories and cytokine pathway activation. However, differences in the magnitude of differentially expressed genes (DEGs) were observed, with A. fumigatus inducing a lower transcriptional effect compared to C. albicans and E. coli. Notably, specific gene signatures associated with cell death were differentially regulated by fungal pathogens, potentially increasing neutrophil susceptibility to autophagy, pyroptosis, and neutrophil extracellular trap (NET) formation. These findings provide valuable insights into the complex immunological responses of neutrophils during fungal infections, offering new avenues for diagnostic and therapeutic strategies, particularly in the management of invasive fungal diseases.},

keywords = {differential expression analysis, fungi, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Heinze:21,

title = {RUNX3 Transcript Variants Have Distinct Roles in Ovarian Carcinoma and Differently Influence Platinum Sensitivity and Angiogenesis},

author = {Karolin Heinze and Martin Hölzer and Martin Ungelenk and Melanie Gerth and Jürgen Thomale and Regine Heller and Claire R. Morden and Kirk J. McManus and Alexander S. Mosig and Matthias Dürst and Ingo B. Runnebaum and Norman Häfner},

doi = {10.3390/cancers13030476},

year  = {2021},

date = {2021-01-26},

urldate = {2021-01-26},

journal = {Cancers},

volume = {13},

number = {3},

pages = {476},

publisher = {MDPI AG},

abstract = {The prognosis of late-stage epithelial ovarian cancer (EOC) patients is affected by chemotherapy response and the malignant potential of the tumor cells. In earlier work, we identified hypermethylation of the runt-related transcription factor 3 gene (RUNX3) as a prognostic biomarker and contrary functions of transcript variants (TV1 and TV2) in A2780 and SKOV3 cells. The aim of the study was to further validate these results and to increase the knowledge about RUNX3 function in EOC. New RUNX3 overexpression models of high-grade serous ovarian cancer (HGSOC) were established and analyzed for phenotypic (IC50 determination, migration, proliferation and angiogenesis assay, DNA damage analysis) and transcriptomic consequences (NGS) of RUNX3 TV1 and TV2 overexpression. Platinum sensitivity was affected by a specific transcript variant depending on BRCA background. RUNX3 TV2 induced an increased sensitivity in BRCA1wt cells (OVCAR3), whereas TV1 increased the sensitivity and induced a G2/M arrest under treatment in BRCA1mut cells (A13-2-12). These different phenotypes relate to differences in DNA repair: homologous recombination deficient A13-2-12 cells show less γH2AX foci despite higher levels of Pt-DNA adducts. RNA-Seq analyses prove transcript variant and cell-line-specific RUNX3 effects. Pathway analyses revealed another clinically important function of RUNX3—regulation of angiogenesis. This was confirmed by thrombospondin1 analyses, HUVEC spheroid sprouting assays and proteomic profiling. Importantly, conditioned media (CM) from RUNX3 TV1 overexpressing A13-2-12 cells induced an increased HUVEC sprouting. Altogether, the presented data support the hypothesis of different functions of RUNX3 transcript variants related to the clinically relevant processes—platinum resistance and angiogenesis. },

keywords = {cancer, differential expression analysis, proteins, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Lataretu:20,

title = {RNAflow: An Effective and Simple RNA-Seq Differential Gene Expression Pipeline Using Nextflow},

author = {Marie Lataretu and Martin Hölzer},

url = {https://github.com/hoelzer-lab/rnaflow},

doi = {10.3390/genes11121487},

year  = {2020},

date = {2020-12-10},

urldate = {2020-01-01},

journal = {Genes},

volume = {11},

number = {12},

pages = {1487},

publisher = {MDPI AG},

abstract = {RNA-Seq enables the identification and quantification of RNA molecules, often with the aim of detecting differentially expressed genes (DEGs). Although RNA-Seq evolved into a standard technique, there is no universal gold standard for these data’s computational analysis. On top of that, previous studies proved the irreproducibility of RNA-Seq studies. Here, we present a portable, scalable, and parallelizable Nextflow RNA-Seq pipeline to detect DEGs, which assures a high level of reproducibility. The pipeline automatically takes care of common pitfalls, such as ribosomal RNA removal and low abundance gene filtering. Apart from various visualizations for the DEG results, we incorporated downstream pathway analysis for common species as Homo sapiens and Mus musculus. We evaluated the DEG detection functionality while using qRT-PCR data serving as a reference and observed a very high correlation of the logarithmized gene expression fold changes.},

keywords = {differential expression analysis, RNA / transcriptomics, software},

pubstate = {published},

tppubtype = {article}

}

@article{Srivastava:20,

title = {Tissue-specific Gene Expression Changes Are Associated with Aging in Mice},

author = {Akash Srivastava and Emanuel Barth and Maria A. Ermolaeva and Madlen Guenther and Christiane Frahm and Manja Marz and Otto W. Witte},

doi = {10.1016/j.gpb.2020.12.001},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Genomics Proteomics Bioinformatics},

volume = {18},

number = {4},

pages = {430--442},

publisher = {Elsevier BV},

abstract = {Aging is a complex process that can be characterized by functional and cognitive decline in an individual. Aging can be assessed based on the functional capacity of vital organs and their intricate interactions with one another. Thus, the nature of aging can be described by focusing on a specific organ and an individual itself. However, to fully understand the complexity of aging, one must investigate not only a single tissue or biological process but also its complex interplay and interdependencies with other biological processes. Here, using RNA-seq, we monitored changes in the transcriptome during aging in four tissues (including brain, blood, skin and liver) in mice at 9 months, 15 months, and 24 months, with a final evaluation at the very old age of 30 months. We identified several genes and processes that were differentially regulated during aging in both tissue-dependent and tissue-independent manners. Most importantly, we found that the electron transport chain (ETC) of mitochondria was similarly affected at the transcriptome level in the four tissues during the aging process. We also identified the liver as the tissue showing the largest variety of differentially expressed genes (DEGs) over time. Lcn2 (Lipocalin-2) was found to be similarly regulated among all tissues, and its effect on longevity and survival was validated using its orthologue in Caenorhabditis elegans. Our study demonstrated that the molecular processes of aging are relatively subtle in their progress, and the aging process of every tissue depends on the tissue’s specialized function and environment. Hence, individual gene or process alone cannot be described as the key of aging in the whole organism.},

keywords = {aging, differential expression analysis, liver, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Mostajo:20,

title = {A comprehensive annotation and differential expression analysis of short and long non-coding RNAs in 16 bat genomes},

author = {Nelly F. Mostajo and Marie Lataretu and Sebastian Krautwurst and Florian Mock and Daniel Desirò and Kevin Lamkiewicz and Maximilian Collatz and Andreas Schoen and Friedemann Weber and Manja Marz and Martin Hölzer},

url = {https://www.rna.uni-jena.de/supplements/bats/index.html},

doi = {10.1093/nargab/lqz006},

year  = {2019},

date = {2019-09-30},

urldate = {2019-09-30},

journal = {NAR Genomics Bioinf},

volume = {2},

number = {1},

pages = {lqz006},

abstract = {Although bats are increasingly becoming the focus of scientific studies due to their unique properties, these exceptional animals are still among the least studied mammals. Assembly quality and completeness of bat genomes vary a lot and especially non-coding RNA (ncRNA) annotations are incomplete or simply missing. Accordingly, standard bioinformatics pipelines for gene expression analysis often ignore ncRNAs such as microRNAs or long antisense RNAs. The main cause of this problem is the use of incomplete genome annotations. We present a complete screening for ncRNAs within 16 bat genomes. NcRNAs affect a remarkable variety of vital biological functions, including gene expression regulation, RNA processing, RNA interference and, as recently described, regulatory processes in viral infections. Within all investigated bat assemblies, we annotated 667 ncRNA families including 162 snoRNAs and 193 miRNAs as well as rRNAs, tRNAs, several snRNAs and lncRNAs, and other structural ncRNA elements. We validated our ncRNA candidates by six RNA-Seq data sets and show significant expression patterns that have never been described before in a bat species on such a large scale. Our annotations will be usable as a resource (rna.uni-jena.de/supplements/bats) for deeper studying of bat evolution, ncRNAs repertoire, gene expression and regulation, ecology and important host–virus interactions.},

keywords = {annotation, assembly, differential expression analysis, evolution, ncRNAs, RNA / transcriptomics, virus host interaction, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Hoelzer:19a,

title = {Virus- and interferon alpha-induced transcriptomes of cells from the microbat \textit{Myotis daubentonii}},

author = {Martin Hölzer and Andreas Schoen and Julia Wulle and Marcel A. Müller and Christian Drosten and Manja Marz and Friedemann Weber},

doi = {10.1016/j.isci.2019.08.016},

year  = {2019},

date = {2019-09-27},

urldate = {2019-01-01},

journal = {iScience},

volume = {19},

pages = {647-661},

publisher = {Elsevier BV},

abstract = {Antiviral interferons (IFN-alpha/beta) are possibly responsible for the high tolerance of bats to zoonotic viruses. Previous studies focused on the IFN system of megabats (suborder Yinpterochiroptera). We present statistically robust RNA sequencing (RNA-seq) data on transcriptomes of cells from the “microbat” Myotis daubentonii (suborder Yangochiroptera) responding at 6 and 24 h to either an IFN-inducing virus or treatment with IFN. Our data reveal genes triggered only by virus, either in both humans and Myotis (CCL4, IFNL3, CH25H), or exclusively in Myotis (STEAP4). Myotis cells also express a series of conserved IFN-stimulated genes (ISGs) and an unusually high paralog number of the antiviral ISG BST2 (tetherin) but lack several ISGs that were described for megabats (EMC2, FILIP1, IL17RC, OTOGL, SLC24A1). Also, in contrast to megabats, we detected neither different IFN-alpha subtypes nor an unusually high baseline expression of IFNs. Thus, Yangochiroptera microbats, represented by Myotis, may possess an IFN system with distinctive features.

},

keywords = {differential expression analysis, RNA / transcriptomics, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Morales-Prieto:19,

title = {Identification of miRNAs and associated pathways regulated by Leukemia Inhibitory Factor in trophoblastic cell lines.},

author = {Diana M. Morales-Prieto and Emanuel Barth and Jose Martín Murrieta-Coxca and Rodolfo R. Favaro and Ruby N. Gutiérrez-Samudio and Wittaya Chaiwangyen and Stephanie Ospina-Prieto and Bernd Gruhn and Ekkehard Schleußner and Manja Marz and Udo R. Markert},

doi = {10.1016/j.placenta.2019.09.005},

year  = {2019},

date = {2019-09-12},

urldate = {2019-09-12},

journal = {Placenta},

volume = {88},

pages = {20--27},

abstract = {Leukemia Inhibitory Factor (LIF) regulates behavior of trophoblast cells and their interaction with immune and endothelial cells. In vitro, trophoblast cell response to LIF may vary depending on the cell model. Reported differences in the miRNA profile of trophoblastic cells may be responsible for these observations. Therefore, miRNA expression was investigated in four trophoblastic cell lines under LIF stimulation followed by in silico analysis of altered miRNAs and their associated pathways. Low density TaqMan miRNA assays were used to quantify levels of 762 mature miRNAs under LIF stimulation in three choriocarcinoma-derived (JEG-3, ACH-3P and AC1-M59) and a trophoblast immortalized (HTR-8/SVneo) cell lines. Expression of selected miRNAs was confirmed in primary trophoblast cells and cell lines by qPCR. Targets and associated pathways of the differentially expressed miRNAs were inferred from the miRTarBase followed by a KEGG Pathway Enrichment Analysis. HTR-8/SVneo and JEG-3 cells were transfected with miR-21-mimics and expression of miR-21 targets was assessed by qPCR. A similar number of miRNAs changed in each tested cell line upon LIF stimulation, however, low coincidence of individual miRNA species was observed and occurred more often among choriocarcinoma-derived cells (complete data set at http://www.ncbi.nlm.nih.gov/geo/ under GEO accession number GSE130489). Altered miRNAs were categorized into pathways involved in human diseases, cellular processes and signal transduction. Six cascades were identified as significantly enriched, including JAK/STAT and TGFB-SMAD. Upregulation of miR-21-3p was validated in all cell lines and primary cells and STAT3 was confirmed as its target. Dissimilar miRNA responses may be involved in differences of LIF effects on trophoblastic cell lines.},

keywords = {differential expression analysis, ncRNAs, pregnancy},

pubstate = {published},

tppubtype = {article}

}

@article{Gerresheim:19,

title = {Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling},

author = {Gesche Gerresheim and Jochen Bathke and Audrey Michel and Dmitri E. Andreev and Lyudmila Shalamova and Oliver Rossbach and Pan Hu and Dieter Glebe and Markus Fricke and Manja Marz and Alexander Goesmann and Stephen Kiniry and Pavel Baranov and Ivan Shatsky and Michael Niepmann},

doi = {10.3390/ijms20061321},

year  = {2019},

date = {2019-03-15},

urldate = {2019-03-15},

journal = {Int J Mol Sci},

volume = {20},

number = {6},

pages = {1321},

publisher = {MDPI AG},

abstract = {Background: Hepatitis C virus (HCV) infects human liver hepatocytes, often leading to liver cirrhosis and hepatocellular carcinoma (HCC). It is believed that chronic infection alters host gene expression and favors HCC development. In particular, HCV replication in Endoplasmic Reticulum (ER) derived membranes induces chronic ER stress. How HCV replication affects host mRNA translation and transcription at a genome wide level is not yet known. Methods: We used Riboseq (Ribosome Profiling) to analyze transcriptome and translatome changes in the Huh-7.5 hepatocarcinoma cell line replicating HCV for 6 days. Results: Established viral replication does not cause global changes in host gene expression—only around 30 genes are significantly differentially expressed. Upregulated genes are related to ER stress and HCV replication, and several regulated genes are known to be involved in HCC development. Some mRNAs (PPP1R15A/GADD34, DDIT3/CHOP, and TRIB3) may be subject to upstream open reading frame (uORF) mediated translation control. Transcriptional downregulation mainly affects mitochondrial respiratory chain complex core subunit genes. Conclusion: After establishing HCV replication, the lack of global changes in cellular gene expression indicates an adaptation to chronic infection, while the downregulation of mitochondrial respiratory chain genes indicates how a virus may further contribute to cancer cell-like metabolic reprogramming (“Warburg effect”) even in the hepatocellular carcinoma cells used here. },

keywords = {cancer, differential expression analysis, liver, RNA structure, virus host interaction, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Chen:18,

title = {Cohesin-mediated NF-κB signaling limits hematopoietic stem cell self-renewal in aging and inflammation},

author = {Zhiyang Chen and Elias Moris Amro and Friedrich Becker and Martin Hölzer and Seyed Mohammad Mahdi Rasa and Sospeter Ngoci Njeru and Bing Han and Simone Di Sanzo and Yulin Chen and Duozhuang Tang and Si Tao and Ronny Haenold and Marco Groth and Vasily S. Romanov and Joanna M. Kirkpatrick and Johann M. Kraus and Hans A. Kestler and Manja Marz and Alessandro Ori and Francesco Neri and Yohei Morita and K. Lenhard Rudolph},

doi = {10.1084/jem.20181505},

year  = {2018},

date = {2018-12-07},

urldate = {2018-01-01},

journal = {J Exp Med},

volume = {216},

number = {1},

pages = {152--175},

publisher = {Rockefeller University Press},

abstract = {Organism aging is characterized by increased inflammation and decreased stem cell function, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells (HSPCs) exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signaling, which increases chromatin accessibility in the vicinity of NF-κB target genes in response to inflammation. Rad21 is required for normal differentiation, but limits self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB–dependent manner. HSCs from aged mice fail to down-regulate Rad21/cohesin and inflammation/differentiation signals in the resolution phase of inflammation. Inhibition of cohesin/NF-κB reverts hypersensitivity of aged HSPCs to inflammation-induced differentiation and myeloid-biased HSCs with disrupted/reduced expression of Rad21/cohesin are increasingly selected during aging. Together, Rad21/cohesin-mediated NF-κB signaling limits HSPC function during aging and selects for cohesin-deficient HSCs with myeloid-skewed differentiation.},

keywords = {aging, differential expression analysis, DNA / genomics},

pubstate = {published},

tppubtype = {article}

}

@article{Gerst:18,

title = {PCAGO: An interactive web service to analyze RNA-Seq data with principal component analysis},

author = {Ruman Gerst and Martin Hölzer},

url = {https://github.com/rnajena/pcago-unified},

doi = {10.1101/433078},

year  = {2018},

date = {2018-10-03},

urldate = {2018-10-03},

journal = {bioRxiv},

pages = {433078},

publisher = {Cold Spring Harbor Laboratory},

abstract = {The initial characterization and clustering of biological samples is a critical step in the analysis of any transcriptomics study. In many studies, principal component analysis (PCA) is the clustering algorithm of choice to predict the relationship of samples or cells based solely on differential gene expression. In addition to the pure quality evaluation of the data, a PCA can also provide initial insights into the biological background of an experiment and help researchers to interpret the data and design the subsequent computational steps accordingly. However, to avoid misleading clusterings and interpretations, an appropriate selection of the underlying gene sets to build the PCA and the choice of the most fitting principal components for the visualization are crucial parts. Here, we present PCAGO, an easy-to-use and interactive tool to analyze gene quantification data derived from RNA sequencing experiments with PCA. The tool includes features such as read-count normalization, filtering of read counts by gene annotation, and various visualization options. In addition, PCAGO helps to select appropriate parameters such as the number of genes and principal components to create meaningful visualizations.},

keywords = {annotation, differential expression analysis, RNA / transcriptomics, software},

pubstate = {published},

tppubtype = {article}

}

@article{Riege:17,

title = {Massive Effect on LncRNAs in Human Monocytes During Fungal and Bacterial Infections and in Response to Vitamins A and D},

author = {Konstantin Riege and Martin Hölzer and Tilman E Klassert and Emanuel Barth and Julia Bräuer and Maximilian Collatz and Franziska Hufsky and Nelly F. Mostajo and Magdalena Stock and Bertram Vogel and Hortense Slevogt and Manja Marz},

doi = {10.1038/srep40598},

year  = {2017},

date = {2017-01-17},

urldate = {2017-01-17},

journal = {Sci Rep},

volume = {7},

pages = {40598},

abstract = {Mycoses induced by C.albicans or A.fumigatus can cause important host damage either by deficient or exaggerated immune response. Regulation of chemokine and cytokine signaling plays a crucial role for an adequate inflammation, which can be modulated by vitamins A and D. Non-coding RNAs (ncRNAs) as transcription factors or cis-acting antisense RNAs are known to be involved in gene regulation. However, the processes during fungal infections and treatment with vitamins in terms of therapeutic impact are unknown. We show that in monocytes both vitamins regulate ncRNAs involved in amino acid metabolism and immune system processes using comprehensive RNA-Seq analyses. Compared to protein-coding genes, fungi and bacteria induced an expression change in relatively few ncRNAs, but with massive fold changes of up to 4000. We defined the landscape of long-ncRNAs (lncRNAs) in response to pathogens and observed variation in the isoforms composition for several lncRNA following infection and vitamin treatment. Most of the involved antisense RNAs are regulated and positively correlated with their sense protein-coding genes. We investigated lncRNAs with stimulus specific immunomodulatory activity as potential marker genes: LINC00595, SBF2-AS1 (A.fumigatus) and RP11-588G21.2, RP11-394l13.1 (C.albicans) might be detectable in the early phase of infection and serve as therapeutic targets in the future.},

keywords = {bacteria, differential expression analysis, fungi, ncRNAs, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Klassert:17,

title = {Differential Effects of Vitamins A and D on the Transcriptional Landscape of Human Monocytes during Infection},

author = {Tilman E Klassert and Julia Bräuer and Martin Hölzer and Magdalena Stock and Konstantin Riege and Cristina Zubiría-Barrera and Mario M Müller and Silke Rummler and Christine Skerka and Manja Marz and Hortense Slevogt},

doi = {10.1038/srep40599},

year  = {2017},

date = {2017-01-17},

urldate = {2017-01-17},

journal = {Sci Rep},

volume = {7},

pages = {40599},

abstract = {Vitamin A and vitamin D are essential nutrients with a wide range of pleiotropic effects in humans. Beyond their well-documented roles in cellular differentiation, embryogenesis, tissue maintenance and bone/calcium homeostasis, both vitamins have attracted considerable attention due to their association with-immunological traits. Nevertheless, our knowledge of their immunomodulatory potential during infection is restricted to single gene-centric studies, which do not reflect the complexity of immune processes. In the present study, we performed a comprehensive RNA-seq-based approach to define the whole immunomodulatory role of vitamins A and D during infection. Using human monocytes as host cells, we characterized the differential role of both vitamins upon infection with three different pathogens: Aspergillus fumigatus, Candida albicans and Escherichia coli. Both vitamins showed an unexpected ability to counteract the pathogen-induced transcriptional responses. Upon infection, we identified 346 and 176 immune-relevant genes that were regulated by atRA and vitD, respectively. This immunomodulatory activity was dependent on the inflammatory stimulus, allowing us to distinguish regulatory patterns which were specific for each stimulatory setting. Moreover, we explored possible direct and indirect mechanisms of vitamin-mediated regulation of the immune response. Our findings highlight the importance of vitamin-monitoring in critically ill patients. Moreover, our results underpin the potential of atRA and vitD as therapeutic options for anti-inflammatory treatment.},

keywords = {bacteria, differential expression analysis, fungi, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Hoelzer:16,

title = {Differential transcriptional responses to Ebola and Marburg virus infection in bat and human cells},

author = {Martin Hölzer and Verena Krähling and Fabian Amman and Emanuel Barth and Stephan H. Bernhart and Victor A. O. Carmelo and Maximilian Collatz and Gero Doose and Florian Eggenhofer and Jan Ewald and Jörg Fallmann and Lasse M. Feldhahn and Markus Fricke and Juliane Gebauer and Andreas J. Gruber and Franziska Hufsky and Henrike Indrischek and Sabina Kanton and Jörg Linde and Nelly F. Mostajo and Roman Ochsenreiter and Konstantin Riege and Lorena Rivarola-Duarte and Abdullah H. Sahyoun and Sita J. Saunders and Stefan E. Seemann and Andrea Tanzer and Bertram Vogel and Stefanie Wehner and Michael T. Wolfinger and Rolf Backofen and Jan Gorodkin and Ivo Grosse and Ivo Hofacker and Steve Hoffmann and Christoph Kaleta and Peter F. Stadler and Stephan Becker and Manja Marz},

doi = {10.1038/srep34589},

year  = {2016},

date = {2016-10-07},

urldate = {2016-10-07},

journal = {Sci Rep},

volume = {6},

pages = {34589},

abstract = {The unprecedented outbreak of Ebola in West Africa resulted in over 28,000 cases and 11,000 deaths, underlining the need for a better understanding of the biology of this highly pathogenic virus to develop specific counter strategies. Two filoviruses, the Ebola and Marburg viruses, result in a severe and often fatal infection in humans. However, bats are natural hosts and survive filovirus infections without obvious symptoms. The molecular basis of this striking difference in the response to filovirus infections is not well understood. We report a systematic overview of differentially expressed genes, activity motifs and pathways in human and bat cells infected with the Ebola and Marburg viruses, and we demonstrate that the replication of filoviruses is more rapid in human cells than in bat cells. We also found that the most strongly regulated genes upon filovirus infection are chemokine ligands and transcription factors. We observed a strong induction of the JAK/STAT pathway, of several genes encoding inhibitors of MAP kinases (DUSP genes) and of PPP1R15A, which is involved in ER stress-induced cell death. We used comparative transcriptomics to provide a data resource that can be used to identify cellular responses that might allow bats to survive filovirus infections.},

keywords = {differential expression analysis, ncRNAs, RNA / transcriptomics, virus host interaction, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Bauer:14,

title = {Transcriptomic immune response of the cotton stainer \textit{Dysdercus fasciatus} to experimental elimination of vitamin-supplementing intestinal symbionts},

author = {Eugen Bauer and Hassan Salem and Manja Marz and Heiko Vogel and Martin Kaltenpoth},

url = {http://www.ebi.ac.uk/ena/data/view/PRJEB6171},

doi = {10.1371/journal.pone.0114865},

year  = {2014},

date = {2014-12-09},

urldate = {2014-12-09},

journal = {PLoS One},

volume = {9},

pages = {e114865},

abstract = {The acquisition and vertical transmission of bacterial symbionts plays an important role in insect evolution and ecology. However, the molecular mechanisms underlying the stable maintenance and control of mutualistic bacteria remain poorly understood. The cotton stainer Dysdercus fasciatus harbours the actinobacterial symbionts Coriobacterium glomerans and Gordonibacter sp. in its midgut. The symbionts supplement limiting B vitamins and thereby significantly contribute to the host's fitness. In this study, we experimentally disrupted the symbionts' vertical transmission route and performed comparative transcriptomic analyses of genes expressed in the gut of aposymbiotic (symbiont-free) and control individuals to study the host immune response in presence and absence of the mutualists. Annotation of assembled cDNA reads identified a considerable number of genes involved in the innate immune system, including different protein isoforms of several immune effector proteins (specifically i-type lysozyme, defensin, hemiptericin, and pyrrhocoricin), suggesting the possibility for a highly differentiated response towards the complex resident microbial community. Gene expression analyses revealed a constitutive expression of transcripts involved in signal transduction of the main insect immune pathways, but differential expression of certain antimicrobial peptide genes. Specifically, qPCRs confirmed the significant down-regulation of c-type lysozyme and up-regulation of hemiptericin in aposymbiotic individuals. The high expression of c-type lysozyme in symbiont-containing bugs may serve to lyse symbiont cells and thereby harvest B-vitamins that are necessary for subsistence on the deficient diet of Malvales seeds. Our findings suggest a sophisticated host response to perturbation of the symbiotic gut microbiota, indicating that the innate immune system not only plays an important role in combating pathogens, but also serves as a communication interface between host and symbionts.},

keywords = {annotation, assembly, bacteria, differential expression analysis, insects, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Salem:14,

title = {Vitamin supplementation by gut symbionts ensures metabolic homeostasis in an insect host},

author = {Hassan Salem and Eugen Bauer and Anja S Strauss and Heiko Vogel and Manja Marz and Martin Kaltenpoth},

doi = {10.1098/rspb.2014.1838},

year  = {2014},

date = {2014-12-07},

urldate = {2014-12-07},

journal = {Proc Biol Sci},

volume = {281},

pages = {20141838},

abstract = {Despite the demonstrated functional importance of gut microbes, our understanding of how animals regulate their metabolism in response to nutritionally beneficial symbionts remains limited. Here, we elucidate the functional importance of the African cotton stainer's (Dysdercus fasciatus) association with two actinobacterial gut symbionts and subsequently examine the insect's transcriptional response following symbiont elimination. In line with bioassays demonstrating the symbionts' contribution towards host fitness through the supplementation of B vitamins, comparative transcriptomic analyses of genes involved in import and processing of B vitamins revealed an upregulation of gene expression in aposymbiotic (symbiont-free) compared with symbiotic individuals; an expression pattern that is indicative of B vitamin deficiency in animals. Normal expression levels of these genes, however, can be restored by either artificial supplementation of B vitamins into the insect's diet or reinfection with the actinobacterial symbionts. Furthermore, the functional characterization of the differentially expressed thiamine transporter 2 through heterologous expression in Xenopus laevis oocytes confirms its role in cellular uptake of vitamin B1. These findings demonstrate that despite an extracellular localization, beneficial gut microbes can be integral to the host's metabolic homeostasis, reminiscent of bacteriome-localized intracellular mutualists.},

keywords = {bacteria, differential expression analysis, insects, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}