title: The NF-κB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells.
abstract: 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.
authors.affiliation: Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Poppe
authors.affiliation: Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Wittig
authors.affiliation: Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Liane
authors.initials: L
authors.lastname: Jurida
authors.affiliation: Institute for Genetics, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Marek
authors.initials: M
authors.lastname: Bartkuhn
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Wilhelm
authors.affiliation: Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Müller
authors.affiliation: Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Beuerlein
authors.affiliation: Institute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Karl
authors.affiliation: Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Sabin
authors.initials: S
authors.lastname: Bhuju
authors.affiliation: Institute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: John
authors.initials: J
authors.lastname: Ziebuhr
authors.affiliation: Institute of Biochemistry, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: M Lienhard
authors.initials: ML
authors.lastname: Schmitz
authors.affiliation: Rudolf Buchheim Institute of Pharmacology, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kracht
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D028941:Coronavirus 229E, Human; D018352:Coronavirus Infections / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D061346:Laser Capture Microdissection; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D002843:Chromatin; D016328:NF-kappa B