Epigenetic Changes Induced by Bacteroides fragilis Toxin

Infect Immun. 2019 May 21;87(6):e00447-18. doi: 10.1128/IAI.00447-18. Print 2019 Jun.

Abstract

Enterotoxigenic Bacteroides fragilis (ETBF) is a Gram-negative, obligate anaerobe member of the gut microbial community in up to 40% of healthy individuals. This bacterium is found more frequently in people with colorectal cancer (CRC) and causes tumor formation in the distal colon of multiple intestinal neoplasia (Apcmin/+ ) mice; tumor formation is dependent on ETBF-secreted Bacteroides fragilis toxin (BFT). Because of the extensive data connecting alterations in the epigenome with tumor formation, initial experiments attempting to connect BFT-induced tumor formation with methylation in colon epithelial cells (CECs) have been performed, but the effect of BFT on other epigenetic processes, such as chromatin structure, remains unexplored. Here, the changes in gene expression (transcriptome sequencing [RNA-seq]) and chromatin accessibility (assay for transposase-accessible chromatin using sequencing) induced by treatment of HT29/C1 cells with BFT for 24 and 48 h were examined. Our data show that several genes are differentially expressed after BFT treatment and that these changes relate to the interaction between bacteria and CECs. Further, sites of increased chromatin accessibility are associated with the location of enhancers in CECs and the binding sites of transcription factors in the AP-1/ATF family; they are also enriched for common differentially methylated regions (DMRs) in CRC. These data provide insight into the mechanisms by which BFT induces tumor formation and lay the groundwork for future in vivo studies to explore the impact of BFT on nuclear structure and function.

Keywords: Bacteroides fragilis; chromatin; colon cancer; epigenetics; transcriptome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Toxins / metabolism
  • Bacterial Toxins / toxicity*
  • Bacteroides Infections / genetics*
  • Bacteroides Infections / metabolism
  • Bacteroides Infections / microbiology*
  • Bacteroides fragilis / genetics
  • Bacteroides fragilis / metabolism*
  • Cell Line, Tumor
  • Colon / microbiology
  • Colorectal Neoplasms / etiology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / microbiology*
  • Epigenesis, Genetic*
  • Humans
  • Metalloendopeptidases / metabolism
  • Metalloendopeptidases / toxicity*
  • Methylation
  • Mice

Substances

  • Bacterial Toxins
  • Bacteroides fragilis toxin
  • Metalloendopeptidases