Chapter 8 : Phasevarions: an Emerging Paradigm in Epigenetic Gene Regulation in Host-Adapted Mucosal Pathogens

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This chapter discusses the molecular mechanisms of phase variation and the possible roles of phase variable restriction-modification (R-M) systems in bacterial pathogens and reveals how a number of phase-variable type III R-M systems have evolved to have a new and distinct function in gene regulation that results in generation of a diverse bacterial population. Phase variation via simple tandem repeats is by far the most common mechanism of phase variation. Phase variation mediated by DNA methylation is different from the mechanisms. While these mechanisms result from changes in the genome, DNA methylation is epigenetic, meaning that while the phenotype differs the DNA sequence remains unaltered. The fundamental characteristic of the DNA methylation-dependent phase-variable systems is that the methylation state of the target site affects the DNA binding of a regulatory protein, which directly regulates transcription. Importantly, a distinct is associated with a hypervirulent clonal lineage of meningococci, and its phasevarion includes genes suggested to be virulence factors. The presence of multiple phase-variable alleles suggests the possibility of distinct phasevarions existing within each strain, each regulating a different set of genes. The chapter proposes that the phase-variable methylation has arisen due to the selective advantage conferred by the phase-varion enabling random switching of an organism between two distinct cell types. In organisms with multiple phasevarions switching independently, multiple differentiated cell types can be generated.

Citation: Srikhanta Y, Peak I, Jennings M. 2013. Phasevarions: an Emerging Paradigm in Epigenetic Gene Regulation in Host-Adapted Mucosal Pathogens, p 156-170. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch8
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Figure 1

Phase variation as a result of slipped-strand mispairing in simple tandem repeats and its effects on gene transcription and translation. (A) Repeat sequences in the promoter region (regions 1 and 2) or within a gene (region 3) can lead to phase variation by effecting transcription initiation and translation. (B) The presence of an ON number of homopolymeric tract repeats [poly(C) tract] in the promoter region of the gene of enables transcription to proceed. A loss of repeat units modifies the spacing between the −35 promoter and −10 promoter sequence preventing transcription initiation ( ). (C) Effect on the translation product of a one-unit deletion due to slipped-strand mispairing in the homopolymeric tract repeat sequence [pol(G) tract] in the coding sequence of the gene of . A deletion changes the reading frame, which results in a premature stop codon (asterisk), leading to the expression of a truncated form of the protein ( ). Adapted from van der Woude and Baumler, 2004. doi:10.1128/9781555818524.ch8f1

Citation: Srikhanta Y, Peak I, Jennings M. 2013. Phasevarions: an Emerging Paradigm in Epigenetic Gene Regulation in Host-Adapted Mucosal Pathogens, p 156-170. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch8
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Figure 2

Schematic representation of differences in the phase variation properties of individual contingency genes, the phasevarion and Dam methylation. (A) Phase variation of an individual gene. Phase variation via changes in repeat length affects translation (repeats within the gene) or transcription initiation (repeats within the promoter region), leading to reversible, altered expression of a single protein and resulting in the presence or absence of that protein. Random switching of many individual genes leads to a large number of alternate combinations of surface components, resulting in diverse populations. (B) Phase variation via Dam methylation. During DNA replication, competition between Dam and a DNA binding regulatory protein forms DNA methylation patterns that control gene expression at a target site. The target site's methylation state affects the DNA binding of a regulatory protein, which directly regulates transcription. (C) Phasevarion ()-mediated control of multiple genes. Phase variation via changes in repeat length within the gene results in altered expression of genes that contain a specific sequence recognized by , affecting their transcriptional control. Thus, multiple genes can be under the control of the phasevarion, depending on the methylation state of the genome, resulting in diverse populations. Methylated sites are indicated by black squares and unmethylated sites by white squares. Black shapes represent increase gene expression and white shapes represent decreased gene expression. doi:10.1128/9781555818524.ch8f2

Citation: Srikhanta Y, Peak I, Jennings M. 2013. Phasevarions: an Emerging Paradigm in Epigenetic Gene Regulation in Host-Adapted Mucosal Pathogens, p 156-170. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch8
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Figure 3

Effect of phase variation on expression of the gene. (A) Phenotypic validation that :: gene expression is dependent on phase variation of the gene. Rd:: colonies with the 5′-AGTC-3′ repeat tract in frame with the ON ATG (resulting in active Mod) were white, indicating low :: expression. Colonies which phase varied to a blue phenotype (example indicated with an arrow) were observed and picked, and the repeat region was sequenced to determine if change in :: expression correlated with phase variation. All blue colonies were found to have switched from ON (40 repeats) to be in frame with either the OFF with 41 repeats or OFF with 39 repeats. All colonies that switched back from blue to white were found to be in frame (40 repeats). (B) Beta-galactosidase assays showing quantitative differences in the level of :: gene expression resulting from mod repeat tract changes (ON, OFF, or OFF). A fivefold difference in expression was observed between ON and OFF. (C) Schematic diagram showing that translation of the gene is initiated from one of three frames (ON [40], OFF [39 or 41]) depending on the number of 5′-AGTC-3′ repeats. doi:10.1128/9781555818524.ch8f3

Citation: Srikhanta Y, Peak I, Jennings M. 2013. Phasevarions: an Emerging Paradigm in Epigenetic Gene Regulation in Host-Adapted Mucosal Pathogens, p 156-170. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch8
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Figure 4

genes of and . The methylase () genes, restriction endonuclease () genes, and repeat regions that mediate phase variation are indicated. Also shown are the conserved, characteristic motifs found within type III R-M systems, which include in the catalytic region (DPPY) and the AdoMet (methyl donor) binding pocket (FXGXG) ( ), and in the ATP binding motif (TGxGKT), the motif linked to ATP hydrolysis (DEAH), and the endonuclease domain ( ). The and genes are colored to indicate differences in homology between both genes and both genes, respectively. A variable region within (highlighted in stripes) contains the DNA recognition domain ( ). Strains and accession numbers that define the alleles are shown to the left. n, indicates the number of repeats. A black circle on a line and black square on a line indicate the positions of a frameshift mutation and large deletion, respectively. doi:10.1128/9781555818524.ch8f4

Citation: Srikhanta Y, Peak I, Jennings M. 2013. Phasevarions: an Emerging Paradigm in Epigenetic Gene Regulation in Host-Adapted Mucosal Pathogens, p 156-170. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch8
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Table 1

Phase variation mechanisms

Citation: Srikhanta Y, Peak I, Jennings M. 2013. Phasevarions: an Emerging Paradigm in Epigenetic Gene Regulation in Host-Adapted Mucosal Pathogens, p 156-170. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch8

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