The NF-κB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells

PLoS Pathog. 2017 Mar 29;13(3):e1006286. doi: 10.1371/journal.ppat.1006286. eCollection 2017 Mar.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chromatin / physiology*
  • Chromatin Immunoprecipitation
  • Coronavirus 229E, Human*
  • Coronavirus Infections / genetics*
  • Gene Expression Regulation
  • Humans
  • Immunoblotting
  • Laser Capture Microdissection
  • Microscopy, Fluorescence
  • NF-kappa B / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Polymerase Chain Reaction
  • Transcriptome*


  • Chromatin
  • NF-kappa B

Grant support

This work was supported by grants from the Deutsche Forschungsgemeinschaft Kr1143/7-3, KR1141/9-1 (KLIFO309), TRR81/2 (B02) and SFB1021 (C02) (to MK). The work of MLS is supported by the grants SFB1021 (C01), TRR81/2 (A07), SCHM 1417/8-3, SCHM 1417/9-1. Work from both laboratories is further supported by the Excellence Cluster Cardio-Pulmonary System (ECCPS) and the LOEWE/UGMLC program. The work of JZ is supported by grants from the Deutsche Forschungsgemeinschaft ZI618/6-1 (KLIFO309) and SFB1021 (A01, B01). Additional funding was provided by the central core project Z02 of SFB1021 (to JW) and Z01 of TRR81 (to MB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.