Systematic Analysis of REBASE Identifies Numerous Type I Restriction-Modification Systems with Duplicated, Distinct
            <i>hsdS</i>
            Specificity Genes That Can Switch System Specificity by Recombination

Atack, John M.; Guo, Chengying; Litfin, Thomas; Yang, Long; Blackall, P. J.; Zhou, Yaoqi; Jennings, Michael P.

doi:10.1128/msystems.00497-20

Cited by 20 publications

(35 citation statements)

References 44 publications

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“…A thorough understanding of phase variation of gene expression, and in particular of phasevarions, is required in order to determine the stably expressed antigenic repertoire of a bacterial species. The prevalence of phase-variable methyltransferases across the bacterial domain demonstrates that phasevarions are a widespread contingency strategy (22,45,46) and that characterization of these systems is imperative in order to rationally design effective vaccines that only target stably expressed antigens in the organisms where they are present.…”

Section: Discussionmentioning

confidence: 99%

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

Tram

Jen

Phillips

et al. 2021

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Streptococcus suis is a significant cause of bacterial meningitis in humans, particularly in Southeast Asia, and is a leading cause of respiratory and invasive disease in pigs. Phase-variable DNA methyltransferases, associated with restriction-modification (R-M) systems, are a source of epigenetic gene regulation, controlling the expression of multiple genes. These systems are known as phasevarions (phase-variable regulons) and have been characterized in many host-adapted bacterial pathogens. We recently described the presence of a Type III DNA methyltransferase in S. suis, ModS, which contains a simple sequence repeat (SSR) tract within the open reading frame of the modS gene and which differed in length between individual strains. We also observed that multiple allelic variants of the modS gene were present in a population of S. suis isolates. Here, we demonstrate that a biphasic ON-OFF switching of expression occurs in the two most common ModS alleles, ModS1 and ModS2, and that switching is dependent on SSR tract length. Furthermore, we show using single-molecule real-time (SMRT) sequencing that ModS1 and ModS2 are active methyltransferases in S. suis. ON-OFF switching of each ModS allele results in the regulation of distinct phasevarions, with the ModS2 phasevarion impacting growth patterns and antibiotic resistance. This is the first demonstration of a phase-variable Type III DNA methyltransferase in a Gram-positive organism that controls a phasevarion. Characterizing the phenotypic effects of phasevarions in S. suis is key to understanding pathogenesis and the development of future vaccines. IMPORTANCE Streptococcus suis is a causative agent of meningitis, polyarthritis, and polyserositis in swine, and it is a major cause of zoonotic meningitis in humans. Here, we investigate epigenetic gene regulation in S. suis by multiple phasevarions controlled by the phase-variable Type III DNA methyltransferase ModS. This is the first characterized example of a Type III R-M system regulating a phasevarion in a Gram-positive organism. We demonstrate that biphasic ON-OFF switching of ModS expression results in differences in bacterial growth and antibiotic resistance. Understanding the effects of ModS phase variation is required to determine the stably expressed antigenic repertoire of S. suis, which will direct and inform the development of antimicrobial treatments and vaccines against this important pathogen.

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Section: Discussionmentioning

confidence: 99%

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

Tram

Jen

Phillips

et al. 2021

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“…Phasevarions can be identified by known markers of phase variation, such as simple sequence repeats (SSRs) within promoters or gene bodies and hsdS genes flanked by inverted repeats. Systematic surveys have identified 13.8% Type I and 17.4% Type III RMSs as being potentially phase variable (22)(23)(24). Several clinically relevant pathogens such as Helicobacter pylori (25,26), Neisseria meningitidis (27), Neisseria gonorrhoeae (28,29), Haemophilus influenzae (30,31), Moraxella catarrhalis (32,33), and Kingella kingae (34) harbor such phase variable RMSs.…”

Section: Introductionmentioning

confidence: 99%

Methylation by multiple type I restriction modification systems avoids influencing gene regulation in uropathogenicEscherichia coli

Mehershahi

Chen

2021

Preprint

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DNA methylation is a common epigenetic mark that influences transcriptional regulation, and therefore cellular phenotype, across all domains of life, extending also to bacterial virulence. Both orphan methyltransferases and those from restriction modification systems (RMSs) have been co-opted to regulate virulence epigenetically in many bacteria. However, the potential regulatory role of DNA methylation mediated by archetypal Type I systems in Escherichia coli has never been studied. We demonstrated that removal of DNA methylated mediated by three different Escherichia coli Type I RMSs in three distinct E. coli strains had no detectable effect on gene expression or growth in a screen of 1190 conditions. Additionally, deletion of the Type I RMS EcoUTI in UTI89, a prototypical cystitis strain of E. coli, which led to loss of methylation at >750 sites across the genome, had no detectable effect on virulence in a murine model of ascending urinary tract infection (UTI). Finally, introduction of two heterologous Type I RMSs into UTI89 also resulted in no detectable change in gene expression or growth phenotypes. These results stand in sharp contrast with many reports of RMSs regulating gene expression in other bacteria, leading us to propose the concept of “regulation avoidance” for these E. coli Type I RMSs. We hypothesize that regulation avoidance is a consequence of evolutionary adaptation of both the RMSs and the E. coli genome. Our results provide a clear and (currently) rare example of regulation avoidance for Type I RMSs in multiple strains of E. coli, further study of which may provide deeper insights into the evolution of gene regulation and horizontal gene transfer.Author summaryDNA methylation is perhaps the most common epigenetic modification, and it is commonly associated with gene regulation (in nearly all organisms) and virulence (particularly well studied in bacteria). Regarding bacterial virulence, the current DNA methylation literature has focused primarily on orphan methyltransferases or phasevariable restriction modification systems (RMSs). Interestingly, no reports have studied the potential regulatory role of the first RMS discovered, the Type I RMS EcoKI. We used transcriptomics, Phenotype Microarrays, and a murine model of urinary tract infection to screen for functional consequences due to Type I methylation in three unrelated strains of E. coli. Remarkably, we found zero evidence for any epigenetic regulation mediated by these Type I RMSs. Thus, these Type I RMSs appear to function exclusively in host defense against incoming DNA (the canonical function of RMSs), while the methylation status of many hundreds of the corresponding recognition sites has no detectable impact on gene expression or any phenotypes. This led us to the concept of “regulation avoidance” by such DNA methyltransferases, which contrasts with the current literature on bacterial epigenetics. Our study hints at the existence of an entire class of regulation avoidant systems, which provides new perspectives on methylation-mediated gene regulation and bacterial genome evolution.

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“…In order to thoroughly characterise each phasevarion, further analysis will be needed. It will also be important to characterisation the phasevarions controlled by other modS alleles; in previous work we showed that a third (22,43,44), and that characterisation of these systems is imperative in order to rationally design effective vaccines that only target stably expressed antigens in the organisms where they are present.…”

Section: Discussionmentioning

confidence: 99%

“…A thorough understanding of phase variation of gene expression, and in particular phasevarions, is required in order to determine the stably expressed antigenic repertoire of a bacterial species. The prevalence of phase variable methyltransferases across the bacterial domain demonstrates that phasevarions are a widespread contingency strategy (22,43,44), and that characterisation of these systems is imperative in order to rationally design effective vaccines that only target stably expressed antigens in the organisms where they are present.…”

Section: Ms Is a Technique Which Quantitates Protein Expression Based On Abundance (41)mentioning

confidence: 99%

Streptococcus suisencodes multiple allelic variants of a phase-variable Type III DNA methyltransferase, ModS, that control distinct phasevarions

Tram

Jen

Phillips

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Streptococcus suis is a significant cause of bacterial meningitis in humans, particularly in S.E. Asia, and is a leading cause of respiratory and invasive disease in pigs. Phase-variable DNA methyltransferases, associated with Restriction-Modification (R-M) systems, are a source of epigenetic gene regulation, controlling the expression of multiple genes. These systems are known as phasevarions (phase-variable regulons), and have been characterised in many host-adapted bacterial pathogens. We recently described the presence of a Type III DNA methyltransferase in S. suis, ModS, which contains a simple sequence repeat (SSR) tract within the open reading frame of the modS gene, and which varied in length between individual strains. We also observed multiple allelic variants of the modS gene were present in a population of S. suis isolates. Here, we demonstrate that a biphasic ON-OFF switching of expression occurs in the two most common ModS alleles, ModS1 and ModS2, and that switching is dependent on SSR tract length. Further, we show that ModS1 and ModS2 are active methyltransferases in S. suis using Single-Molecule, Real Time (SMRT) sequencing. ON-OFF switching of each ModS allele results in the regulation of distinct phasevarions, with the ModS2 phasevarion impacting growth patterns and antibiotic resistance. This is the first demonstration of a phase-variable Type III DNA methyltransferase in a Gram-positive organism that controls a phasevarion. Characterising the phenotypic effects of phasevarions in S. suis is key to understanding pathogenesis and the development of future vaccines.ImportanceStreptococcus suis is a causative agent of meningitis, polyarthritis and polyserositis in swine, and is a major cause of zoonotic meningitis in humans. Here we investigate epigenetic gene regulation in S. suis by multiple phasevarions controlled by the phase-variable Type III DNA methyltransferase ModS. This is the first characterised example of a Type III R-M system regulating a phasevarion in a Gram-positive organism. We demonstrate that biphasic ON-OFF switching of ModS expression results in differences in bacterial growth and antibiotic resistance. Understanding the effects of ModS phase variation is required to determine the stably expressed antigenic repertoire of S. suis, which will direct and inform the development of antimicrobial treatments and vaccines against this important pathogen.

show abstract

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

Cited by 20 publications

References 44 publications

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

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

Methylation by multiple type I restriction modification systems avoids influencing gene regulation in uropathogenicEscherichia coli

Streptococcus suisencodes multiple allelic variants of a phase-variable Type III DNA methyltransferase, ModS, that control distinct phasevarions

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