Phasevarion Mediated Epigenetic Gene Regulation in Helicobacter pylori

Yogitha N Srikhanta,Jayde A Gawthorne,Jason A Steen,Michael P Jennings,Roy M Robins-Browne,Rebecca J Gorrell,Terry Kwok,Sean M Grimmond,Holger Bruggemann

doi:10.1371/journal.pone.0027569

Abstract

Many host-adapted bacterial pathogens contain DNA methyltransferases (mod genes) that are subject to phase-variable expression (high-frequency reversible ON/OFF switching of gene expression). In Haemophilus influenzae and pathogenic Neisseria, the random switching of the modA gene, associated with a phase-variable type III restriction modification (R-M) system, controls expression of a phase-variable regulon of genes (a “phasevarion”), via differential methylation of the genome in the modA ON and OFF states. Phase-variable type III R-M systems are also found in Helicobacter pylori, suggesting that phasevarions may also exist in this key human pathogen. Phylogenetic studies on the phase-variable type III modH gene revealed that there are 17 distinct alleles in H. pylori, which differ only in their DNA recognition domain. One of the most commonly found alleles was modH5 (16% of isolates). Microarray analysis comparing the wild-type P12modH5 ON strain to a P12ΔmodH5 mutant revealed that six genes were either up- or down-regulated, and some were virulence-associated. These included flaA, which encodes a flagella protein important in motility and hopG, an outer membrane protein essential for colonization and associated with gastric cancer. This study provides the first evidence of this epigenetic mechanism of gene expression in H. pylori. Characterisation of H. pylori modH phasevarions to define stable immunological targets will be essential for vaccine development and may also contribute to understanding H. pylori pathogenesis.

Highlights

The host-adapted pathogen Helicobacter pylori is the most common cause of bacterial infection worldwide [1,2] and is an important etiologic agent of gastritis, peptic ulcers, and gastric cancer [3,4]
While phase-variation is typically associated with genes encoding surface structures, several host-adapted bacterial pathogens, including H. pylori, have DNA methyltransferases associated with type III restriction modification (R-M)
We have previously reported that Helicobacter strains, like the pathogenic Neisseria, contain multiple phase-variable type III R-M systems [9]

Summary

Introduction

The host-adapted pathogen Helicobacter pylori is the most common cause of bacterial infection worldwide [1,2] and is an important etiologic agent of gastritis, peptic ulcers, and gastric cancer [3,4]. In order to adapt its physiology to its environment and ensure survival, H. pylori has evolved molecular mechanisms for generating genetic variation [5]. Phase-variation is commonly mediated by mutations in simple tandem DNA repeats in the open reading frame or promoter region of genes encoding surface expressed virulence determinants [6]. While phase-variation is typically associated with genes encoding surface structures, several host-adapted bacterial pathogens, including H. pylori, have DNA methyltransferases (mod genes) associated with type III restriction modification (R-M)

Methods

Results

Conclusion