Open AccessModulation of the Host Cell Transcriptome and Epigenome by Fusobacterium nucleatum
Author(s) -
Cody A Despins,
Scott D. Brown,
Avery Robinson,
Andrew J. Mungall,
Emma AllenVercoe,
Robert A. Holt
Publication year - 2021
Publication title -
mbio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.562
H-Index - 121
eISSN - 2161-2129
pISSN - 2150-7511
DOI - 10.1128/mbio.02062-21
Subject(s) - fusobacterium nucleatum , biology , transcriptome , chromatin immunoprecipitation , downregulation and upregulation , ccl20 , cancer research , gene expression , microbiology and biotechnology , gene , immunology , genetics , inflammation , chemokine , porphyromonas gingivalis , chemokine receptor , promoter , bacteria
ABSTRACT 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 TNF , CXCL8 , CXCL1 , and CCL20 . Furthermore, we identified genes strongly upregulated in a cell line-specific manner. In HCE cells, overexpressed genes included UBD and DUOX2 / DUOXA2 , associated with p53 degradation-mediated proliferation and intestinal reactive oxygen species (ROS) production, respectively. In HCAE cells, overexpressed genes included EFNA1 and LIF , two genes commonly upregulated in colorectal cancer and associated with poor patient outcomes, and PTGS2 ( COX2 ), 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.