Modulation of the Host Cell Transcriptome and Epigenome by Fusobacterium nucleatum

• Published in: mBio 2021-10, Vol.12 (5), p.e0206221-e0206221
• Main Authors: Despins, Cody A, Brown, Scott D, Robinson, Avery V, Mungall, Andrew J, Allen-Vercoe, Emma, Holt, Robert A
• Format: Article
• Language: English
• Subjects: Cell Line; Chemokine CCL20 - genetics; Chemokine CCL20 - metabolism; Dual Oxidases - genetics; Dual Oxidases - metabolism; Endothelial Cells - metabolism; Endothelial Cells - microbiology; Epigenome; Epithelial Cells - metabolism; Epithelial Cells - microbiology; Fusobacterium Infections - genetics; Fusobacterium Infections - metabolism; Fusobacterium Infections - microbiology; Fusobacterium nucleatum - genetics; Fusobacterium nucleatum - physiology; Host-Pathogen Interactions; Humans; Pathogenesis and Host Response; Research Article; Transcriptome
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mBio.02062-21

Fusobacterium nucleatum is a ubiquitous opportunistic pathogen with an emerging role as an oncomicrobe in colorectal cancer and other cancer settings. F. nucleatum can adhere to and invade host cells in a manner that varies across F. nucleatum strains and host cell phenotypes. Here, we performed pairwise cocultures between three F. nucleatum strains and two immortalized primary host cell types (human colonic epithelial [HCE] cells and human carotid artery endothelial [HCAE] cells) followed by transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) to investigate transcriptional and epigenetic host cell responses. We observed that F. nucleatum-induced host cell transcriptional modulation involves strong upregulation of genes related to immune migration and inflammatory processes, such as , , , and . Furthermore, we identified genes strongly upregulated in a cell line-specific manner. In HCE cells, overexpressed genes included and / , associated with p53 degradation-mediated proliferation and intestinal reactive oxygen species (ROS) production, respectively. In HCAE cells, overexpressed genes included and , two genes commonly upregulated in colorectal cancer and associated with poor patient outcomes, and ( ), a gene associated with the protective effect of aspirin in the colorectal cancer setting. Interestingly, we also observed downregulation of numerous histone modification genes upon F. nucleatum exposure. We used the ChIP-seq data to annotate chromatin states genome wide and found significant chromatin remodeling following F. nucleatum exposure in HCAE cells, with increased frequencies of active enhancer and low-signal/quiescent states. Thus, our results highlight increased inflammation and chemokine gene expression as conserved host cell responses to F. nucleatum exposure and extensive host cell epigenomic changes specific to host cell type. Fusobacterium nucleatum is a bacterium normally found in the healthy oral cavity but also has an emerging role in colorectal cancer and other cancer settings. The host-microbe interactions of F. nucleatum and its involvement in tumor initiation, progression, and treatment resistance are not fully understood. We explored host cell changes that occur in response to F. nucleatum. We identified key genes differentially expressed in response to various conditions of F. nucleatum exposure and determined that the conserved host cell response to F. nucleatum was dominated by increased infl