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2. Mechanism and consequences of herpes simplex virus 1-mediated regulation of host mRNA alternative polyadenylation.

Author

Wang, Xiuye, Liu, Liang, Whisnant, Adam W, Hennig, Thomas, Djakovic, Lara, Haque, Nabila, Bach, Cindy, Sandri-Goldin, Rozanne M, Erhard, Florian, Friedel, Caroline C, Dölken, Lars, and Shi, Yongsheng

Subjects
Genetics, Developmental Biology
Abstract

Eukaryotic gene expression is extensively regulated by cellular stress and pathogen infections. We have previously shown that herpes simplex virus 1 (HSV-1) and several cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII) in host genes and that the viral immediate early factor ICP27 plays an important role in HSV-1-induced DoTT. Here, we show that HSV-1 infection also leads to widespread changes in alternative polyadenylation (APA) of host mRNAs. In the majority of cases, polyadenylation shifts to upstream poly(A) sites (PAS), including many intronic PAS. Mechanistically, ICP27 contributes to HSV-1-mediated APA regulation. HSV-1- and ICP27-induced activation of intronic PAS is sequence-dependent and does not involve general inhibition of U1 snRNP. HSV1-induced intronic polyadenylation is accompanied by early termination of RNAPII. HSV-1-induced mRNAs polyadenylated at intronic PAS (IPA) are exported into the cytoplasm while APA isoforms with extended 3' UTRs are sequestered in the nuclei, both preventing the expression of the full-length gene products. Finally we provide evidence that HSV-induced IPA isoforms are translated. Together with other recent studies, our results suggest that viral infection and cellular stresses induce a multi-faceted host response that includes DoTT and changes in APA profiles.

Published
2021

3. Herpes simplex virus blocks host transcription termination via the bimodal activities of ICP27.

Author

Wang, Xiuye, Hennig, Thomas, Whisnant, Adam W, Erhard, Florian, Prusty, Bhupesh K, Friedel, Caroline C, Forouzmand, Elmira, Hu, William, Erber, Luke, Chen, Yue, Sandri-Goldin, Rozanne M, Dölken, Lars, and Shi, Yongsheng

Subjects
Cell Line, Hela Cells, Animals, Humans, Herpesvirus 1, Human, Herpes Simplex, Cleavage And Polyadenylation Specificity Factor, Immediate-Early Proteins, RNA, Messenger, RNA Processing, Post-Transcriptional, Host-Pathogen Interactions, Transcription Termination, Genetic, HeLa Cells, Genetics, Sexually Transmitted Infections, Infectious Diseases, 2.1 Biological and endogenous factors, 2.2 Factors relating to physical environment, Infection, Sexually Transmitted Diseases/Herpes
Abstract

Infection by viruses, including herpes simplex virus-1 (HSV-1), and cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII) in host genes. However, the underlying mechanisms remain unclear. Here, we demonstrate that the HSV-1 immediate early protein ICP27 induces DoTT by directly binding to the essential mRNA 3' processing factor CPSF. It thereby induces the assembly of a dead-end 3' processing complex, blocking mRNA 3' cleavage. Remarkably, ICP27 also acts as a sequence-dependent activator of mRNA 3' processing for viral and a subset of host transcripts. Our results unravel a bimodal activity of ICP27 that plays a key role in HSV-1-induced host shutoff and identify CPSF as an important factor that mediates regulation of transcription termination. These findings have broad implications for understanding the regulation of transcription termination by other viruses, cellular stress and cancer.

Published
2020

4. CDK11 regulates pre-mRNA splicing by phosphorylation of SF3B1

Author

Hluchý, Milan, Gajdušková, Pavla, Ruiz de los Mozos, Igor, Rájecký, Michal, Kluge, Michael, Berger, Benedict-Tilman, Slabá, Zuzana, Potěšil, David, Weiß, Elena, Ule, Jernej, Zdráhal, Zbyněk, Knapp, Stefan, Paruch, Kamil, Friedel, Caroline C., and Blazek, Dalibor

Published
2022
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8. Merkel cell polyomavirus small tumor antigen contributes to immune evasion by interfering with type I interferon signaling.

Author

Ohnezeit, Denise, Huang, Jiabin, Westerkamp, Ute, Brinschwitz, Veronika, Schmidt, Claudia, Günther, Thomas, Czech-Sioli, Manja, Weißelberg, Samira, Schlemeyer, Tabea, Nakel, Jacqueline, Mai, Julia, Schreiner, Sabrina, Schneider, Carola, Friedel, Caroline C., Schwanke, Hella, Brinkmann, Melanie M., Grundhoff, Adam, and Fischer, Nicole

Subjects
VIRAL proteins, INTERFERON regulatory factors, MERKEL cells, MERKEL cell carcinoma, GENE expression, TYPE I interferons
Abstract

Merkel cell polyomavirus (MCPyV) is the causative agent of the majority of Merkel cell carcinomas (MCC). The virus has limited coding capacity, with its early viral proteins, large T (LT) and small T (sT), being multifunctional and contributing to infection and transformation. A fundamental difference in early viral gene expression between infection and MCPyV-driven tumorigenesis is the expression of a truncated LT (LTtr) in the tumor. In contrast, sT is expressed in both conditions and contributes significantly to oncogenesis. Here, we identified novel functions of early viral proteins by performing genome-wide transcriptome and chromatin studies in primary human fibroblasts. Due to current limitations in infection and tumorigenesis models, we mimic these conditions by ectopically expressing sT, LT or LTtr, individually or in combination, at different time points. In addition to its known function in cell cycle and inflammation modulation, we reveal a fundamentally new function of sT. We show that sT regulates the type I interferon (IFN) response downstream of the type I interferon receptor (IFNAR) by interfering with the interferon-stimulated gene factor 3 (ISGF3)-induced interferon-stimulated gene (ISG) response. Expression of sT leads to a reduction in the expression of interferon regulatory factor 9 (IRF9) which is a central component of the ISGF3 complex. We further show that this function of sT is conserved in BKPyV. We provide a first mechanistic understanding of which early viral proteins trigger and control the type I IFN response, which may influence MCPyV infection, persistence and, during MCC progression, regulation of the tumor microenvironment. Author summary: Merkel cell polyomavirus (MCPyV) is the only human polyomavirus that causes cancer in humans. As with all human polyomaviruses, the available infection models are limited. Thus, many processes such as the host response to infection and its regulation by the virus to establish infection and persistence are poorly understood. To better understand this interplay of viral MCPyV proteins, we performed genome-wide transcriptome and chromatin studies in primary human fibroblasts and simulated infection and tumorigenesis conditions by ectopically expressing the early viral proteins individually or in combination at different time points. This allowed us to uncover a novel, previously undescribed function of polyomavirus sT, namely the reduction of the ISG response by affecting the ISGF3 complex, specifically by reducing IRF9 protein levels. This work sheds light on how early viral proteins influence the type I IFN response and how their interplay may affect MCPyV infection, persistence, and MCC progression. [ABSTRACT FROM AUTHOR]

Published
2024
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13. mRNA N1-2'O-methylation by CMTR1 affects NVL2 mRNA splicing

Author

Wolter, Steven, primary, Henning, Thomas, additional, Wallerath, Christina, additional, Schlee-Guimaraes, Thais M, additional, Kirchhoff, Alexander, additional, Urban, Christian, additional, Piras, Antonio, additional, Stukalov, Alexey, additional, Juranek, Stefan, additional, Engelke, Michael, additional, Boehm, Volker, additional, Gehring, Niels H., additional, Hartmann, Gunther, additional, Pichlmair, Andreas, additional, Friedel, Caroline C., additional, Doelken, Lars, additional, and Schlee, Martin, additional

Published
2023
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14. Evolutionarily conserved herpesviral protein interaction networks.

Author

Fossum, Even, Friedel, Caroline C, Rajagopala, Seesandra V, Titz, Björn, Baiker, Armin, Schmidt, Tina, Kraus, Theo, Stellberger, Thorsten, Rutenberg, Christiane, Suthram, Silpa, Bandyopadhyay, Sourav, Rose, Dietlind, von Brunn, Albrecht, Uhlmann, Mareike, Zeretzke, Christine, Dong, Yu-An, Boulet, Hélène, Koegl, Manfred, Bailer, Susanne M, Koszinowski, Ulrich, Ideker, Trey, Uetz, Peter, Zimmer, Ralf, and Haas, Jürgen

Subjects
Hela Cells, Humans, Herpesviridae, Herpesvirus 1, Human, Herpesvirus 3, Human, Muromegalovirus, Herpesvirus 4, Human, Herpesvirus 8, Human, Virion, Viral Proteins, Viral Core Proteins, Immunohistochemistry, Cluster Analysis, Protein Interaction Mapping, Evolution, Molecular, Phylogeny, Signal Transduction, HeLa Cells, Evolution, Molecular, Herpesvirus 1, Human, Herpesvirus 3, Herpesvirus 4, Herpesvirus 8, Virology, Microbiology, Immunology, Medical Microbiology
Abstract

Herpesviruses constitute a family of large DNA viruses widely spread in vertebrates and causing a variety of different diseases. They possess dsDNA genomes ranging from 120 to 240 kbp encoding between 70 to 170 open reading frames. We previously reported the protein interaction networks of two herpesviruses, varicella-zoster virus (VZV) and Kaposi's sarcoma-associated herpesvirus (KSHV). In this study, we systematically tested three additional herpesvirus species, herpes simplex virus 1 (HSV-1), murine cytomegalovirus and Epstein-Barr virus, for protein interactions in order to be able to perform a comparative analysis of all three herpesvirus subfamilies. We identified 735 interactions by genome-wide yeast-two-hybrid screens (Y2H), and, together with the interactomes of VZV and KSHV, included a total of 1,007 intraviral protein interactions in the analysis. Whereas a large number of interactions have not been reported previously, we were able to identify a core set of highly conserved protein interactions, like the interaction between HSV-1 UL33 with the nuclear egress proteins UL31/UL34. Interactions were conserved between orthologous proteins despite generally low sequence similarity, suggesting that function may be more conserved than sequence. By combining interactomes of different species we were able to systematically address the low coverage of the Y2H system and to extract biologically relevant interactions which were not evident from single species.

Published
2009

15. The Cytomegalovirus M35 Protein Directly Binds to the Interferon-β Enhancer and Modulates Transcription of Ifnb1 and Other IRF3-Driven Genes

Author

Schwanke, Hella, primary, Gonçalves Magalhães, Vladimir, additional, Schmelz, Stefan, additional, Wyler, Emanuel, additional, Hennig, Thomas, additional, Günther, Thomas, additional, Grundhoff, Adam, additional, Dölken, Lars, additional, Landthaler, Markus, additional, van Ham, Marco, additional, Jänsch, Lothar, additional, Büssow, Konrad, additional, van den Heuvel, Joop, additional, Blankenfeldt, Wulf, additional, Friedel, Caroline C., additional, Erhard, Florian, additional, and Brinkmann, Melanie M., additional

Published
2023
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16. Integrative functional genomics decodes herpes simplex virus 1

Author

Whisnant, Adam W., Jürges, Christopher S., Hennig, Thomas, Wyler, Emanuel, Prusty, Bhupesh, Rutkowski, Andrzej J., L’hernault, Anne, Djakovic, Lara, Göbel, Margarete, Döring, Kristina, Menegatti, Jennifer, Antrobus, Robin, Matheson, Nicholas J., Künzig, Florian W. H., Mastrobuoni, Guido, Bielow, Chris, Kempa, Stefan, Liang, Chunguang, Dandekar, Thomas, Zimmer, Ralf, Landthaler, Markus, Grässer, Friedrich, Lehner, Paul J., Friedel, Caroline C., Erhard, Florian, and Dölken, Lars

Published
2020
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19. Decoding murine cytomegalovirus

Author

Lodha, Manivel, primary, Muchsin, Ihsan, additional, Jürges, Christopher, additional, Juranic Lisnic, Vanda, additional, L’Hernault, Anne, additional, Rutkowski, Andrzej J., additional, Prusty, Bhupesh K., additional, Grothey, Arnhild, additional, Milic, Andrea, additional, Hennig, Thomas, additional, Jonjic, Stipan, additional, Friedel, Caroline C., additional, Erhard, Florian, additional, and Dölken, Lars, additional

Published
2023
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22. The Cytomegalovirus M35 Protein Modulates Transcription of Ifnb1 and Other IRF3-Driven Genes by Direct Promoter Binding

Author

Schwanke, Hella, primary, Goncalves Magalhaes, Vladimir, additional, Schmelz, Stefan, additional, Wyler, Emanuel, additional, Hennig, Thomas, additional, Guenther, Thomas, additional, Grundhoff, Adam, additional, Doelken, Lars, additional, Landthaler, Markus, additional, van Ham, Marco, additional, Jaensch, Lothar, additional, Buessow, Konrad, additional, van den Heuvel, Joop, additional, Blankenfeldt, Wulf, additional, Friedel, Caroline C., additional, Erhard, Florian, additional, and Brinkmann, Melanie M., additional

Published
2023
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24. Women in the European Virus Bioinformatics Center

Author

Hufsky, Franziska, Abecasis, Ana, Agudelo-Romero, Patricia, Bletsa, Magda, Brown, Katherine, Claus, Claudia, Deinhardt-Emmer, Stefanie, Deng, Li, Friedel, Caroline C, Gismondi, María Inés, Kostaki, Evangelia Georgia, Kühnert, Denise, Kulkarni-Kale, Urmila, Metzner, Karin J, Meyer, Irmtraud M, Miozzi, Laura, Nishimura, Luca, Paraskevopoulou, Sofia, Pérez-Cataluña, Alba, Rahlff, Janina, Thomson, Emma, Tumescheit, Charlotte, van der Hoek, Lia, Van Espen, Lore, Vandamme, Anne-Mieke, Zaheri, Maryam, Zuckerman, Neta, Marz, Manja, Hufsky, Franziska [0000-0002-9489-3182], Abecasis, Ana [0000-0002-3903-5265], Agudelo-Romero, Patricia [0000-0002-3703-4111], Bletsa, Magda [0000-0003-3184-6618], Brown, Katherine [0000-0002-8400-6922], Claus, Claudia [0000-0003-4962-6568], Deinhardt-Emmer, Stefanie [0000-0003-4495-4052], Deng, Li [0000-0003-0225-0663], Friedel, Caroline C [0000-0003-3569-4877], Gismondi, María Inés [0000-0002-2566-1169], Kostaki, Evangelia Georgia [0000-0002-3346-0930], Kühnert, Denise [0000-0002-5657-018X], Kulkarni-Kale, Urmila [0000-0002-1168-2479], Metzner, Karin J [0000-0003-4862-1503], Meyer, Irmtraud M [0000-0002-4048-3479], Miozzi, Laura [0000-0003-0410-8230], Nishimura, Luca [0000-0003-2144-7867], Paraskevopoulou, Sofia [0000-0003-2608-2596], Pérez-Cataluña, Alba [0000-0002-4784-8346], Rahlff, Janina [0000-0002-2132-2709], Thomson, Emma [0000-0003-1482-0889], Tumescheit, Charlotte [0000-0002-7563-5575], van der Hoek, Lia [0000-0003-2803-642X], Van Espen, Lore [0000-0002-3870-4551], Vandamme, Anne-Mieke [0000-0002-6594-2766], Zaheri, Maryam [0000-0003-2777-835X], Zuckerman, Neta [0000-0001-6074-2100], Marz, Manja [0000-0003-4783-8823], Apollo - University of Cambridge Repository, Medical Microbiology and Infection Prevention, AII - Infectious diseases, University of Zurich, Hufsky, Franziska, and Marz, Manja

Subjects
10028 Institute of Medical Virology, virus evolution, virus discovery, Cancer Research, viral ecology, Virus Bioinformatics, Big Data, Networking, Virus Discovery, Virus Evolution, Viral Infection, Transcriptomics, Emerging Viruses, Epidemiology, Viral Ecology, networking, virus bioinformatics, Computational Biology, 610 Medicine & health, 2725 Infectious Diseases, Research Personnel, Europe, emerging viruses, transcriptomics, big data, Viruses, 2406 Virology, 570 Life sciences, biology, Humans, epidemiology, Female, viral infection
Abstract

Viruses are the cause of a considerable burden to human, animal and plant health, while on the other hand playing an important role in regulating entire ecosystems. The power of new sequencing technologies combined with new tools for processing "Big Data" offers unprecedented opportunities to answer fundamental questions in virology. Virologists have an urgent need for virus-specific bioinformatics tools. These developments have led to the formation of the European Virus Bioinformatics Center, a network of experts in virology and bioinformatics who are joining forces to enable extensive exchange and collaboration between these research areas. The EVBC strives to provide talented researchers with a supportive environment free of gender bias, but the gender gap in science, especially in math-intensive fields such as computer science, persists. To bring more talented women into research and keep them there, we need to highlight role models to spark their interest, and we need to ensure that female scientists are not kept at lower levels but are given the opportunity to lead the field. Here we showcase the work of the EVBC and highlight the achievements of some outstanding women experts in virology and viral bioinformatics. ispartof: VIRUSES-BASEL vol:14 issue:7 ispartof: location:Switzerland status: published

Published
2022

27. Murine cytomegalovirus viewer

Author

Muchsin, Ihsan, Lodha, Manivel, Jürges, Christopher S., Juranic-Lisnic, Vanda, L'hernault, Anne, Rutkowski, Andrzej J., Prusty, Bhupesh, Grothey, Arnhild, Hennig, Thomas, Milic, Andrea, Jonjic, Stipan, Friedel, Caroline C., Erhard, Florian, and Dölken, Lars

Abstract

We here provide our MCMV genome browser software containing a state-of-the-art MCMV annotation. Thereby, viral gene expression and all data can be visually examined from the whole genome to single-nucleotide resolution.

Published
2022
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28. Decoding murine cytomegalovirus

Author

Lodha, Manivel, primary, Muchsin, Ihsan, additional, Jürges, Christopher, additional, Lisnic, Vanda Juranic, additional, L’hernault, Anne, additional, Rutkowski, Andrzej J., additional, Prusty, Bhupesh, additional, Grothey, Arnhild, additional, Milic, Andrea, additional, Hennig, Thomas, additional, Jonjic, Stipan, additional, Friedel, Caroline C., additional, Erhard, Florian, additional, and Dölken, Lars, additional

Published
2022
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34. Women in the European Virus Bioinformatics Center

Author

Hufsky, Franziska; https://orcid.org/0000-0002-9489-3182, Abecasis, Ana; https://orcid.org/0000-0002-3903-5265, Agudelo-Romero, Patricia; https://orcid.org/0000-0002-3703-4111, Bletsa, Magda; https://orcid.org/0000-0003-3184-6618, Brown, Katherine; https://orcid.org/0000-0002-8400-6922, Claus, Claudia; https://orcid.org/0000-0003-4962-6568, Deinhardt-Emmer, Stefanie; https://orcid.org/0000-0003-4495-4052, Deng, Li; https://orcid.org/0000-0003-0225-0663, Friedel, Caroline C; https://orcid.org/0000-0003-3569-4877, Gismondi, María Inés; https://orcid.org/0000-0002-2566-1169, Kostaki, Evangelia Georgia; https://orcid.org/0000-0002-3346-0930, Kühnert, Denise; https://orcid.org/0000-0002-5657-018X, Kulkarni-Kale, Urmila; https://orcid.org/0000-0002-1168-2479, Metzner, Karin J; https://orcid.org/0000-0003-4862-1503, Meyer, Irmtraud M; https://orcid.org/0000-0002-4048-3479, Miozzi, Laura; https://orcid.org/0000-0003-0410-8230, Nishimura, Luca; https://orcid.org/0000-0003-2144-7867, Paraskevopoulou, Sofia; https://orcid.org/0000-0003-2608-2596, Pérez-Cataluña, Alba; https://orcid.org/0000-0002-4784-8346, Rahlff, Janina; https://orcid.org/0000-0002-2132-2709, Thomson, Emma; https://orcid.org/0000-0003-1482-0889, Tumescheit, Charlotte; https://orcid.org/0000-0002-7563-5575, van der Hoek, Lia; https://orcid.org/0000-0003-2803-642X, Van Espen, Lore; https://orcid.org/0000-0002-3870-4551, Vandamme, Anne-Mieke; https://orcid.org/0000-0002-6594-2766, Zaheri, Maryam; https://orcid.org/0000-0003-2777-835X, Zuckerman, Neta; https://orcid.org/0000-0001-6074-2100, Marz, Manja; https://orcid.org/0000-0003-4783-8823, Hufsky, Franziska; https://orcid.org/0000-0002-9489-3182, Abecasis, Ana; https://orcid.org/0000-0002-3903-5265, Agudelo-Romero, Patricia; https://orcid.org/0000-0002-3703-4111, Bletsa, Magda; https://orcid.org/0000-0003-3184-6618, Brown, Katherine; https://orcid.org/0000-0002-8400-6922, Claus, Claudia; https://orcid.org/0000-0003-4962-6568, Deinhardt-Emmer, Stefanie; https://orcid.org/0000-0003-4495-4052, Deng, Li; https://orcid.org/0000-0003-0225-0663, Friedel, Caroline C; https://orcid.org/0000-0003-3569-4877, Gismondi, María Inés; https://orcid.org/0000-0002-2566-1169, Kostaki, Evangelia Georgia; https://orcid.org/0000-0002-3346-0930, Kühnert, Denise; https://orcid.org/0000-0002-5657-018X, Kulkarni-Kale, Urmila; https://orcid.org/0000-0002-1168-2479, Metzner, Karin J; https://orcid.org/0000-0003-4862-1503, Meyer, Irmtraud M; https://orcid.org/0000-0002-4048-3479, Miozzi, Laura; https://orcid.org/0000-0003-0410-8230, Nishimura, Luca; https://orcid.org/0000-0003-2144-7867, Paraskevopoulou, Sofia; https://orcid.org/0000-0003-2608-2596, Pérez-Cataluña, Alba; https://orcid.org/0000-0002-4784-8346, Rahlff, Janina; https://orcid.org/0000-0002-2132-2709, Thomson, Emma; https://orcid.org/0000-0003-1482-0889, Tumescheit, Charlotte; https://orcid.org/0000-0002-7563-5575, van der Hoek, Lia; https://orcid.org/0000-0003-2803-642X, Van Espen, Lore; https://orcid.org/0000-0002-3870-4551, Vandamme, Anne-Mieke; https://orcid.org/0000-0002-6594-2766, Zaheri, Maryam; https://orcid.org/0000-0003-2777-835X, Zuckerman, Neta; https://orcid.org/0000-0001-6074-2100, and Marz, Manja; https://orcid.org/0000-0003-4783-8823

Abstract

Viruses are the cause of a considerable burden to human, animal and plant health, while on the other hand playing an important role in regulating entire ecosystems. The power of new sequencing technologies combined with new tools for processing "Big Data" offers unprecedented opportunities to answer fundamental questions in virology. Virologists have an urgent need for virus-specific bioinformatics tools. These developments have led to the formation of the European Virus Bioinformatics Center, a network of experts in virology and bioinformatics who are joining forces to enable extensive exchange and collaboration between these research areas. The EVBC strives to provide talented researchers with a supportive environment free of gender bias, but the gender gap in science, especially in math-intensive fields such as computer science, persists. To bring more talented women into research and keep them there, we need to highlight role models to spark their interest, and we need to ensure that female scientists are not kept at lower levels but are given the opportunity to lead the field. Here we showcase the work of the EVBC and highlight the achievements of some outstanding women experts in virology and viral bioinformatics.

Published
2022

35. Time-resolved single-cell RNA-seq using metabolic RNA labelling

Author

Erhard, Florian; https://orcid.org/0000-0002-3574-6983, Saliba, Antoine-Emmanuel, Lusser, Alexandra, Toussaint, Christophe; https://orcid.org/0000-0003-3419-490X, Hennig, Thomas, Prusty, Bhupesh K; https://orcid.org/0000-0001-7051-4670, Kirschenbaum, Daniel; https://orcid.org/0000-0002-0609-8788, Abadie, Kathleen, Miska, Eric A; https://orcid.org/0000-0002-4450-576X, Friedel, Caroline C; https://orcid.org/0000-0003-3569-4877, Amit, Ido, Micura, Ronald, Dölken, Lars; https://orcid.org/0000-0002-4651-3544, Erhard, Florian; https://orcid.org/0000-0002-3574-6983, Saliba, Antoine-Emmanuel, Lusser, Alexandra, Toussaint, Christophe; https://orcid.org/0000-0003-3419-490X, Hennig, Thomas, Prusty, Bhupesh K; https://orcid.org/0000-0001-7051-4670, Kirschenbaum, Daniel; https://orcid.org/0000-0002-0609-8788, Abadie, Kathleen, Miska, Eric A; https://orcid.org/0000-0002-4450-576X, Friedel, Caroline C; https://orcid.org/0000-0003-3569-4877, Amit, Ido, Micura, Ronald, and Dölken, Lars; https://orcid.org/0000-0002-4651-3544

Abstract

Single-cell RNA sequencing offers snapshots of whole transcriptomes but obscures the temporal RNA dynamics. Here we present single-cell metabolically labeled new RNA tagging sequencing (scNT-seq), a method for massively parallel analysis of newly transcribed and pre-existing mRNAs from the same cell. This droplet microfluidics-based method enables high-throughput chemical conversion on barcoded beads, efficiently marking newly transcribed mRNAs with T-to-C substitutions. Using scNT-seq, we jointly profiled new and old transcriptomes in ~55,000 single cells. These data revealed time-resolved transcription factor activities and cell-state trajectories at the single-cell level in response to neuronal activation. We further determined rates of RNA biogenesis and decay to uncover RNA regulatory strategies during stepwise conversion between pluripotent and rare totipotent two-cell embryo (2C)-like stem cell states. Finally, integrating scNT-seq with genetic perturbation identifies DNA methylcytosine dioxygenase as an epigenetic barrier into the 2C-like cell state. Time-resolved single-cell transcriptomic analysis thus opens new lines of inquiry regarding cell-type-specific RNA regulatory mechanisms.

Published
2022

39. Women in the European Virus Bioinformatics Center

Author

Hufsky, Franziska, Abecasis, Ana, Agudelo-Romero, Patricia, Bletsa, Magda, Brown, Katherine, Claus, Claudia, Deinhardt-Emmer, Stefanie, Deng, Li, Friedel, Caroline C., Gismondi, María Inés, Kostaki, Evangelia Georgia, Kühnert, Denise, Kulkarni-Kale, Urmila, Metzner, Karin J., Meyer, Irmtraud M., Miozzi, Laura, Nishimura, Luca, Paraskevopoulou, Sofia, Pérez-Cataluña, Alba, Rahlff, Janina, Thomson, Emma, Tumescheit, Charlotte, van der Hoek, Lia, Van Espen, Lore, Vandamme, Anne-Mieke, Zaheri, Maryam, Zuckerman, Neta, and Marz, Manja

Subjects
Commentary, virus bioinformatics, big data, networking, virus discovery, virus evolution, viral infection, transcriptomics, emerging viruses, epidemiology, viral ecology, ddc
Published
2021

40. iBRET Screen of the ABCD1 Peroxisomal Network and Mutation-Induced Network Perturbations

Author

Lotz-Havla, Amelie S., primary, Woidy, Mathias, additional, Guder, Philipp, additional, Friedel, Caroline C., additional, Klingbeil, Julian M., additional, Bulau, Ana-Maria, additional, Schultze, Anja, additional, Dahmen, Ilona, additional, Noll-Puchta, Heidi, additional, Kemp, Stephan, additional, Erdmann, Ralf, additional, Zimmer, Ralf, additional, Muntau, Ania C., additional, and Gersting, Søren W., additional

Published
2021
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44. Integrative functional genomics decodes herpes simplex virus 1

Author

Whisnant, Adam W, Jürges, Christopher S, Hennig, Thomas, Wyler, Emanuel, Prusty, Bhupesh, Rutkowski, Andrzej J, L'hernault, Anne, Djakovic, Lara, Göbel, Margarete, Döring, Kristina, Menegatti, Jennifer, Antrobus, Robin, Matheson, Nicholas J, Künzig, Florian WH, Mastrobuoni, Guido, Bielow, Chris, Kempa, Stefan, Liang, Chunguang, Dandekar, Thomas, Zimmer, Ralf, Landthaler, Markus, Grässer, Friedrich, Lehner, Paul J, Friedel, Caroline C, Erhard, Florian, Dölken, Lars, HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany., Whisnant, Adam W [0000-0003-2039-2809], Jürges, Christopher S [0000-0001-5617-6601], Wyler, Emanuel [0000-0002-9884-1806], Prusty, Bhupesh [0000-0001-7051-4670], Djakovic, Lara [0000-0002-9368-9403], Matheson, Nicholas J [0000-0002-3318-1851], Künzig, Florian WH [0000-0003-3730-3905], Mastrobuoni, Guido [0000-0003-4509-1295], Bielow, Chris [0000-0001-5756-3988], Kempa, Stefan [0000-0002-0696-9299], Liang, Chunguang [0000-0002-0305-2522], Dandekar, Thomas [0000-0003-1886-7625], Landthaler, Markus [0000-0002-1075-8734], Friedel, Caroline C [0000-0003-3569-4877], Erhard, Florian [0000-0002-3574-6983], Dölken, Lars [0000-0002-4651-3544], and Apollo - University of Cambridge Repository

Subjects
Gene Expression Regulation, Viral, Biological Products, Genes, Viral, viruses, Computational Biology, Genome, Viral, Genomics, Herpesvirus 1, Human, Fibroblasts, Article, Computational biology and bioinformatics, Open Reading Frames, Protein Domains, Cricetinae, Chlorocebus aethiops, Animals, Humans, Protein Isoforms, Herpes virus, Transcriptome, Ribosomes, Vero Cells
Abstract

The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution., Here, using computational integration of multi-omics data, the authors provide a detailed transcriptome and translatome of herpes simplex virus 1 (HSV-1), including previously unidentified ORFs and N-terminal extensions. The study also provides a HSV-1 genome browser and should be a valuable resource for further research.

Published
2019

46. Diversified transcriptional responses of myeloid and glial cells in spinal cord injury shaped by HDAC3 activity

Author

Wahane, Shalaka, primary, Zhou, Xianxiao, additional, Zhou, Xiang, additional, Guo, Lei, additional, Friedl, Marie-Sophie, additional, Kluge, Michael, additional, Ramakrishnan, Aarthi, additional, Shen, Li, additional, Friedel, Caroline C., additional, Zhang, Bin, additional, Friedel, Roland H., additional, and Zou, Hongyan, additional

Published
2021
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47. Dissecting Herpes Simplex Virus 1-Induced Host Shutoff at the RNA Level

Author

Friedel, Caroline C., primary, Whisnant, Adam W., additional, Djakovic, Lara, additional, Rutkowski, Andrzej J., additional, Friedl, Marie-Sophie, additional, Kluge, Michael, additional, Williamson, James C., additional, Sai, Somesh, additional, Vidal, Ramon Oliveira, additional, Sauer, Sascha, additional, Hennig, Thomas, additional, Grothey, Arnhild, additional, Milić, Andrea, additional, Prusty, Bhupesh K., additional, Lehner, Paul J., additional, Matheson, Nicholas J., additional, Erhard, Florian, additional, and Dölken, Lars, additional

Published
2021
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49. Mechanism and consequences of herpes simplex virus 1-mediated regulation of host mRNA alternative polyadenylation

Author

Wang, Xiuye, primary, Liu, Liang, additional, Whisnant, Adam W., additional, Hennig, Thomas, additional, Djakovic, Lara, additional, Haque, Nabila, additional, Bach, Cindy, additional, Sandri-Goldin, Rozanne M., additional, Erhard, Florian, additional, Friedel, Caroline C., additional, Dölken, Lars, additional, and Shi, Yongsheng, additional

Published
2020
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