The NF-κB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells
| Autor: | Marek Bartkuhn, Michael Kracht, Sabin Bhuju, Nadja Karl, Knut Beuerlein, John Ziebuhr, Michael Poppe, Helmut Müller, Liane Jurida, M. Lienhard Schmitz, Sascha Wittig, Jochen Wilhelm |
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| Přispěvatelé: | Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany. |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Gene Expression Biochemistry Polymerase Chain Reaction 0302 clinical medicine Coronavirus 229E Human Gene expression Transcriptional regulation Post-Translational Modification Phosphorylation Biology (General) Oligonucleotide Array Sequence Analysis Regulation of gene expression biology Chromosome Biology Microbial Genetics NF-kappa B Chromatin 030220 oncology & carcinogenesis Host cell cytoplasm Viral Genetics Epigenetics Coronavirus Infections Research Article Chromatin Immunoprecipitation Human coronavirus 229E QH301-705.5 Immunology DNA transcription Immunoblotting Laser Capture Microdissection Microbiology Cell Line 03 medical and health sciences Virology Genetics Humans Gene Regulation Enhancer Molecular Biology Transcription factor Host Cells Biology and Life Sciences Proteins Cell Biology RC581-607 biology.organism_classification Molecular biology Viral Replication 030104 developmental biology Viral Gene Expression Gene Expression Regulation Microscopy Fluorescence Parasitology Immunologic diseases. Allergy Transcriptome Viral Transmission and Infection |
| Zdroj: | PLoS Pathogens, Vol 13, Iss 3, p e1006286 (2017) PLOS Pathogens PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Coronavirus replication takes place in the host cell cytoplasm and triggers inflammatory gene expression by poorly characterized mechanisms. To obtain more insight into the signals and molecular events that coordinate global host responses in the nucleus of coronavirus-infected cells, first, transcriptome dynamics was studied in human coronavirus 229E (HCoV-229E)-infected A549 and HuH7 cells, respectively, revealing a core signature of upregulated genes in these cells. Compared to treatment with the prototypical inflammatory cytokine interleukin(IL)-1, HCoV-229E replication was found to attenuate the inducible activity of the transcription factor (TF) NF-κB and to restrict the nuclear concentration of NF-κB subunits by (i) an unusual mechanism involving partial degradation of IKKβ, NEMO and IκBα and (ii) upregulation of TNFAIP3 (A20), although constitutive IKK activity and basal TNFAIP3 expression levels were shown to be required for efficient virus replication. Second, we characterized actively transcribed genomic regions and enhancers in HCoV-229E-infected cells and systematically correlated the genome-wide gene expression changes with the recruitment of Ser5-phosphorylated RNA polymerase II and prototypical histone modifications (H3K9ac, H3K36ac, H4K5ac, H3K27ac, H3K4me1). The data revealed that, in HCoV-infected (but not IL-1-treated) cells, an extensive set of genes was activated without inducible p65 NF-κB being recruited. Furthermore, both HCoV-229E replication and IL-1 were shown to upregulate a small set of genes encoding immunomodulatory factors that bind p65 at promoters and require IKKβ activity and p65 for expression. Also, HCoV-229E and IL-1 activated a common set of 440 p65-bound enhancers that differed from another 992 HCoV-229E-specific enhancer regions by distinct TF-binding motif combinations. Taken together, the study shows that cytoplasmic RNA viruses fine-tune NF-κB signaling at multiple levels and profoundly reprogram the host cellular chromatin landscape, thereby orchestrating the timely coordinated expression of genes involved in multiple signaling, immunoregulatory and metabolic processes. Author summary Coronaviruses are major human and animal pathogens. They belong to a family of plus-strand RNA viruses that have extremely large genomes and encode a variety of proteins involved in virus-host interactions. The four common coronaviruses (HCoV-229E, NL63, OC43, HKU1) cause mainly upper respiratory tract infections, while zoonotic coronaviruses (SARS-CoV and MERS-CoV) cause severe lung disease, including acute respiratory distress syndrome (ARDS). The molecular basis for this fundamentally different pathology is incompletely understood. Our study provides a genome-wide investigation of epigenetic changes occurring in response to HCoV-229E. We identify at high resolution a large number of regulatory regions in the genome of infected cells that coordinate de novo gene transcription. Many of these genes have immunomodulatory functions and, most likely, contribute to limiting viral replication, while other factors may promote viral replication. The study provides an intriguing example of a virus that completes its entire life cycle in the cytoplasm while sending multiple signals to the nuclear chromatin compartment to adjust the host cell repertoire of transcribed genes. The approach taken in this study is expected to provide a suitable framework for future studies aimed at dissecting and comparing host responses to representative coronaviruses with different pathogenic potential in humans. |
| Databáze: | OpenAIRE |
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