Phasevarion Mediated Epigenetic Gene Regulation in Helicobacter pylori

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.

• Publication year

  2011

• Venue

  PLoS ONE

• Publication date

  2011-12-05

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pone.0027569PMID 22162751PMCID 3230613
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Strain-specific genes of Helicobacter pylori: genome evolution driven by a novel type IV secretion system and genomic island transfer

  2010cited by this paper
• Complexomics Study of Two Helicobacter pylori Strains of Two Pathological Origins

  2010cited by this paper
• The phasevarion: phase variation of type III DNA methyltransferases controls coordinated switching in multiple genes

  2010cited by this paper
• Phasevarions Mediate Random Switching of Gene Expression in Pathogenic Neisseria

  2009cited by this paper
• Helicobacter pylori evolution during progression from chronic atrophic gastritis to gastric cancer and its impact on gastric stem cells

  2008cited by this paper
• Phase variable type III restriction‐modification systems of host‐adapted bacterial pathogens

  2007cited by this paper
• Haemophilus influenzae phasevarions have evolved from type III DNA restriction systems into epigenetic regulators of gene expression

  2007cited by this paper
• Functional Analysis of the M.HpyAIV DNA Methyltransferase of Helicobacter pylori

  2007cited by this paper
• High allelic diversity in the methyltransferase gene of a phase variable type III restriction-modification system has implications for the fitness of Haemophilus influenzae

  2006cited by this paper
• Helicobacter infection and gastric neoplasia

  2006cited by this paper
• The phasevarion: a genetic system controlling coordinated, random switching of expression of multiple genes.

  2005cited by this paper
• Restriction of DNA encoding selectable markers decreases the transformation efficiency of Helicobacter pylori.

  2005cited by this paper
• Helicobacter pylori Flagellar Hook-Filament Transition Is Controlled by a FliK Functional Homolog Encoded by the Gene HP0906

  2005cited by this paper
• Evasion of Toll-like receptor 5 by flagellated bacteria.

  2005cited by this paper
• Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity.

  2004cited by this paper
• Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments

  2004cited by this paper
• Helicobacter pylori flagellins have very low intrinsic activity to stimulate human gastric epithelial cells via TLR5.

  2003cited by this paper
• Identification and Characterization of Helicobacter pylori Genes Essential for Gastric Colonization

  2003influential reference
• Statistical issues in cDNA microarray data analysis.

  2003cited by this paper
• Colonization of Germ-free Transgenic Mice with Genotyped Helicobacter pylori Strains from a Case-Control Study of Gastric Cancer Reveals a Correlation between Host Responses and HsdS Components of Type I Restriction-Modification Systems* 210

  2002cited by this paper
• Complex restriction enzymes: NTP-driven molecular motors.

  2002cited by this paper
• Transcriptional Phase Variation of a Type III Restriction-Modification System in Helicobacter pylori

  2002cited by this paper
• Specificities of Eleven Different DNA Methyltransferases of Helicobacter pylori Strain 26695

  2001cited by this paper
• Characterization of four members of a multigene family encoding outer membrane proteins of Helicobacter pylori and their potential for vaccination.

  2001cited by this paper
• Comparative genomics of the restriction-modification systems in Helicobacter pylori

  2001cited by this paper
• The disease spectrum of Helicobacter pylori: the immunopathogenesis of gastroduodenal ulcer and gastric cancer.

  2000cited by this paper
• Functional analysis of putative restriction-modification system genes in the Helicobacter pylori J99 genome.

  2000cited by this paper
• Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori

  1999cited by this paper
• Helicobacter pylori Physiology Predicted from Genomic Comparison of Two Strains

  1999cited by this paper
• Short-Sequence DNA Repeats in Prokaryotic Genomes

  1998cited by this paper
• Perspectives Series: Host/Pathogen Interactions

  1997cited by this paper
• Helicobacter pylori

  1997cited by this paper
• Microbial genetics: The tinkerer's evolving tool-box

  1997cited by this paper
• vaccine in The Netherlands . persons vaccinated with inactivated poliovirus Poliovirus-specific immunoglobulin A in

  1997cited by this paper
• Colonization of gnotobiotic piglets by Helicobacter pylori deficient in two flagellin genes

  1996cited by this paper
• Comparative ultrastructural and functional studies of Helicobacter pylori and Helicobacter mustelae flagellin mutants: both flagellin subunits, FlaA and FlaB, are necessary for full motility in Helicobacter species

  1995cited by this paper
• Type III restriction endonucleases translocate DNA in a reaction driven by recognition site‐specific ATP hydrolysis.

  1995cited by this paper
• Cloning and genetic characterization of the Helicobacter pylori and Helicobacter mustelae flaB flagellin genes and construction of H. pylori flaA- and flaB-negative mutants by electroporation-mediated allelic exchange

  1993cited by this paper
• Biology of DNA restriction.

  1993cited by this paper
• Identification, characterization, and spatial localization of two flagellin species in Helicobacter pylori flagella

  1991cited by this paper
• Type III DNA restriction and modification systems EcoP1 and EcoP15. Nucleotide sequence of the EcoP1 operon, the EcoP15 mod gene and some EcoP1 mod mutants.

  1988influential reference
• Methylation and cleavage sequences of the EcoP1 restriction-modification enzyme.

  1979cited by this paper
• DNA restriction and modification mechanisms in bacteria.

  1971cited by this paper

• Whole genome sequence analysis of Helicobacter pylori isolates reveals incomplete characterization of antimicrobial resistance mechanisms

  2025cites this paper
• Understanding prokaryotic adaptation through advanced DNA methylation detection techniques

  2025cites this paper
• Mechanisms and Implications of Phenotypic Switching in Bacterial Pathogens.

  2024cites this paper
• Uncovering the link between the SpnIII restriction modification system and LuxS in Streptococcus pneumoniae meningitis isolates

  2023cites this paper
• Genome and population dynamics during chronic infection with Helicobacter pylori.

  2023cites this paper
• Antimicrobial resistance and mechanisms of epigenetic regulation

  2023cites this paper
• Methylome evolution suggests lineage-dependent selection in the gastric pathogen Helicobacter pylori

  2023cites this paper
• The Helicobacter pylori methylome is acid-responsive due to regulation by the two-component system ArsRS and the type I DNA methyltransferase HsdM1 (HP0463)

  2023cites this paper
• Actinobacillus pleuropneumoniae encodes multiple phase-variable DNA methyltransferases that control distinct phasevarions

  2022cites this paper
• Role of DNA modifications in Mycoplasma gallisepticum

  2022cites this paper
• Adherence of Nontypeable Haemophilus influenzae to Cells and Substrates of the Airway Is Differentially Regulated by Individual ModA Phasevarions

  2022cites this paper
• Genomic diversity of Helicobacter pylori populations from different regions of the human stomach

  2022cites this paper
• Epigenetics and Helicobacter pylori

  2022cites this paper
• Kingella kingae RtxA Cytotoxin in the Context of Other RTX Toxins

  2022cites this paper
• ModA phasevarions regulate adherence of non-typeable Haemophilus influenzae to the host airway in a tissue-specific manner

  2022cites this paper
• Epigenetic-Mediated Antimicrobial Resistance: Host versus Pathogen Epigenetic Alterations

  2022cites this paper
• Marine DNA methylation patterns are associated with microbial community composition and inform virus-host dynamics

  2022cites this paper
• Phase-variable Type I methyltransferase M.NgoAV from Neisseria gonorrhoeae FA1090 regulates phasevarion expression and gonococcal phenotype

  2022cites this paper
• DNA methylation by three Type I restriction modification systems of Escherichia coli does not influence gene regulation of the host bacterium

  2021cites this paper
• Community-wide epigenetics provides novel perspectives on the ecology and evolution of marine microbiome

  2021cites this paper
• Methylation Motifs in Promoter Sequences May Contribute to the Maintenance of a Conserved m5C Methyltransferase in Helicobacter pylori

  2021cites this paper
• Characterization of the Type I Restriction Modification System Broadly Conserved among Group A Streptococci

  2021cites this paper
• Deciphering the Role of Epigenetic Reprogramming in Host-Pathogen Interactions

  2021cites this paper
• Reversible gene silencing through frameshift indels and frameshift scars provide adaptive plasticity for Mycobacterium tuberculosis

  2021cites this paper
• Beyond Restriction Modification: Epigenomic Roles of DNA Methylation in Prokaryotes.

  2021cites this paper
• Transcriptional Profile of Helicobacter pylori Virulence Genes in Patients with Gastritis and Gastric Cancer

  2021cites this paper
• Prokaryotic DNA methylation and its functional roles

  2021cites this paper
• Streptococcus suis Encodes Multiple Allelic Variants of a Phase-Variable Type III DNA Methyltransferase, ModS, That Control Distinct Phasevarions

  2021cites this paper
• Methylation by multiple type I restriction modification systems avoids influencing gene regulation in uropathogenic Escherichia coli

  2021cites this paper
• Epigenetics of infectious diseases

  2021cites this paper
• References

  2020cites this paper
• Comparative Analysis of Streptococcus pneumoniae Type I Restriction-Modification Loci: Variation in hsdS Gene Target Recognition Domains

  2020cites this paper
• In Vivo Genome and Methylome Adaptation of cag-Negative Helicobacter pylori during Experimental Human Infection

  2020cites this paper
• Systematic Analysis of REBASE Identifies Numerous Type I Restriction-Modification Systems with Duplicated, Distinct hsdS Specificity Genes That Can Switch System Specificity by Recombination

  2020cites this paper
• The Pangenome: Diversity, Dynamics and Evolution of Genomes

  2020cites this paper
• Epigenetic Regulation of Virulence and Immunoevasion by Phase-Variable Restriction-Modification Systems in Bacterial Pathogens.

  2020cites this paper
• Networking and Specificity-Changing DNA Methyltransferases in Helicobacter pylori

  2020cites this paper
• Bacterial Epigenomics: Epigenetics in the Age of Population Genomics

  2020cites this paper
• Systematic analysis of REBASE identifies numerous Type I restriction-modification systems that contain duplicated, variable hsdS specificity genes that randomly switch methyltransferase specificity by recombination

  2020cites this paper
• A Bacterial Epigenetic Switch in Non-typeable Haemophilus influenzae Modifies Host Immune Response During Otitis Media

  2020cites this paper
• A positive perspective on DNA methylation: regulatory functions of DNA methylation outside of host defense in Gram-positive bacteria

  2020cites this paper
• Tetramerization at low pH licenses DNA methylation activity of M.HpyAXI in the presence of acid stress.

  2020cites this paper
• Evolved to Vary: Genome and Epigenome Variation in the human pathogen Helicobacter pylori.

  2020cites this paper
• Promiscuous DNA cleavage by HpyAII endonuclease is modulated by the HNH catalytic residues

  2020cites this paper
• Phase-variable bacterial loci: how bacteria gamble to maximise fitness in changing environments.

  2019cites this paper
• Phasevarions of bacterial pathogens - phase-variable epigenetic regulators evolving from restriction-modification systems.

  2019cites this paper
• Antibiotic Resistance and Epigenetics: More to It than Meets the Eye

  2019cites this paper
• Non-typeable Haemophilus influenzae isolates from patients with chronic obstructive pulmonary disease contain new phase-variable modA methyltransferase alleles controlling phasevarions

  2019cites this paper
• The Moraxella catarrhalis phase-variable DNA methyltransferase ModM3 is an epigenetic regulator that affects bacterial survival in an in vivo model of otitis media

  2019cites this paper
• DNA sequence repeats identify numerous Type I restriction‐modification systems that are potential epigenetic regulators controlling phase‐variable regulons; phasevarions

  2019cites this paper
• Phase Variation of Streptococcus pneumoniae

  2019cites this paper
• Genetic variation regulates the activation and specificity of Restriction-Modification systems in Neisseria gonorrhoeae

  2019cites this paper
• N4-cytosine DNA methylation regulates transcription and pathogenesis in Helicobacter pylori

  2018cites this paper
• Epigenetic Regulation Alters Biofilm Architecture and Composition in Multiple Clinical Isolates of Nontypeable Haemophilus influenzae

  2018cites this paper
• Streptococcus suis contains multiple phase-variable methyltransferases that show a discrete lineage distribution

  2018cites this paper
• N4-cytosine DNA methylation regulates transcription and pathogenesis in Helicobacter pylori

  2018cites this paper
• Deciphering bacterial epigenomes using modern sequencing technologies

  2018cites this paper
• The core genome m5C methyltransferase JHP1050 (M.Hpy99III) plays an important role in orchestrating gene expression in Helicobacter pylori

  2018cites this paper
• Phasevarions of Bacterial Pathogens: Methylomics Sheds New Light on Old Enemies.

  2018cites this paper
• A survey of Type III restriction-modification systems reveals numerous, novel epigenetic regulators controlling phase-variable regulons; phasevarions

  2018cites this paper
• Genomics and population dynamics of phase variable genes in Campylobacter

  2017cites this paper
• Accessory genetic content in Campylobacter jejuni ST21CC isolates from feces and blood.

  2017cites this paper
• Phasevarion-Regulated Virulence in the Emerging Pediatric Pathogen Kingella kingae

  2017cites this paper
• Phase-variable methylation and epigenetic regulation by type I restriction-modification systems.

  2017cites this paper
• Methylomic and phenotypic analysis of the ModH5 phasevarion of Helicobacter pylori

  2017influential citation
• The Helicobacter pylori Methylome: Roles in Gene Regulation and Virulence.

  2017cites this paper
• griffith . edu . au Specificity of the ModA 11 , ModA 12 and ModD 1 epigenetic regulator N 6-adenine DNA methyltransferases of Neisseria meningitidis

  2017influential citation
• The ModA2 Phasevarion of nontypeable Haemophilus influenzae Regulates Resistance to Oxidative Stress and Killing by Human Neutrophils

  2017cites this paper
• Phase variation of DNA methyltransferases and the regulation of virulence and immune evasion in the pathogenic Neisseria.

  2017cites this paper
• Investigation of the influence of phase variable restriction modification systems and lipooligosaccharide epitopes on resistance of Haemophilus influenzae to infection by bacteriophage

  2017cites this paper
• Epigenetic Phase Variation in Bacterial Pathogens

  2017cites this paper
• The Type I Restriction Modification System SpnIII of Streptococcus pneumoniae

  2017cites this paper
• The modA10 phasevarion of nontypeable Haemophilus influenzae R2866 regulates multiple virulence-associated traits.

  2016cites this paper
• The Capricious Nature of Bacterial Pathogens: Phasevarions and Vaccine Development

  2016influential citation
• The Campylobacter jejuni Oxidative Stress Regulator RrpB Is Associated with a Genomic Hypervariable Region and Altered Oxidative Stress Resistance

  2016cites this paper
• Characterisation of Streptococcus pneumoniae opacity phase variation

  2016cites this paper
• Population Evolution of Helicobacter pylori through Diversification in DNA Methylation and Interstrain Sequence Homogenization.

  2016cites this paper
• Epigenetics Mediated by Restriction Modification Systems

  2016cites this paper
• Phase variation of a Type IIG restriction-modification enzyme alters site-specific methylation patterns and gene expression in Campylobacter jejuni strain NCTC11168

  2016cites this paper
• ModA2 Phasevarion Switching in Nontypeable Haemophilus influenzae Increases the Severity of Experimental Otitis Media.

  2016cites this paper
• [Diversity in genome and epigenome of Helicobacter pylori].

  2015cites this paper
• Chapter 68 – Helicobacter pylori

  2015cites this paper
• FREQUENCY OF HELICOBACTER PYLORI (HP) INFECTION IN CHILDREN WITH RECURRENT ABDOMINAL PAIN (RAP)

  2015cites this paper
• The modA10 phasevarion of Nontypeable H. influenzae R2866 regulates multiple virulence-associated traits

  2015cites this paper
• A Cytosine Methytransferase Modulates the Cell Envelope Stress Response in the Cholera Pathogen

  2015cites this paper
• A biphasic epigenetic switch controls immunoevasion, virulence and niche adaptation in non-typeable Haemophilus influenzae

  2015cites this paper
• Selection and Counterselection of Hia Expression Reveals a Key Role for Phase-Variable Expression of Hia in Infection Caused by Nontypeable Haemophilus influenzae.

  2015cites this paper
• Microevolution of Virulence-Related Genes in Helicobacter pylori Familial Infection

  2015cites this paper
• Identification of DNA Methyltransferase Genes in Human Pathogenic Bacteria by Comparative Genomics

  2015cites this paper
• The complete methylome of Helicobacter pylori UM032

  2015cites this paper
• Type III Methyltransferase M.NgoAX from Neisseria gonorrhoeae FA1090 Regulates Biofilm Formation and Interactions with Human Cells

  2015cites this paper
• Specificity of the ModA11, ModA12 and ModD1 epigenetic regulator N6-adenine DNA methyltransferases of Neisseria meningitidis

  2015influential citation
• Complete Genome Sequence of Mycoplasma bovoculi Strain M165/69T (ATCC 29104)

  2014cites this paper
• Phase-variable restriction/modification systems are required for Helicobacter pylori colonization

  2014cites this paper
• qDNAmod: a statistical model-based tool to reveal intercellular heterogeneity of DNA modification from SMRT sequencing data

  2014cites this paper
• ModM DNA methyltransferase methylome analysis reveals a potential role for Moraxella catarrhalis phasevarions in otitis media

  2014cites this paper
• Phase Variation in Plant-Associated Pseudomonads

  2014cites this paper
• Virulence Factors of Helicobacter pylori: A Review

  2014cites this paper
• Plasticity in Plant-Growth-Promoting and Phytopathogenic Bacteria

  2014cites this paper
• Persistence of Helicobacter pylori Infection: Genetic and Epigenetic Diversity

  2014influential citation