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

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in

Phasevarions: an Emerging Paradigm in Epigenetic Gene Regulation in Host-Adapted Mucosal Pathogens, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555818524/9781555816766_Chap08-1.gif /docserver/preview/fulltext/10.1128/9781555818524/9781555816766_Chap08-2.gif


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
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
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
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
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
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
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
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 4
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
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Ahmad, I.,, and D. N. Rao. 1994. Interaction of EcoP15I DNA methyltransferase with oligonucleotides containing the asymmetric sequence 5'-CAGCAG-3'. J. Mol. Biol. 242:378388.
2. Andersen-Nissen, E.,, K. D. Smith,, K. L. Strobe,, S. L. Barrett,, B. T. Cookson,, S. M. Logan,, and A. Aderem. 2005. Evasion of Toll-like receptor 5 by flagellated bacteria. Proc. Natl. Acad. Sci. USA 102:92479252.
3. Ando, T.,, Q. Xu,, M. Torres,, K. Kusugami,, D. A. Israel,, and M. J. Blaser. 2000. Restriction-modification system differences in Helicobacter pylori are a barrier to interstrain plasmid transfer. Mol. Microbiol. 37:10521065.
4. Arber, W. 1974. DNA modification and restriction. Prog. Nucleic Acid Res. Mol. Biol. 14:137.
5. Arber, W.,, and D. Dussoix. 1962. Host specificity of DNA produced by Escherichia coli. I. Host controlled modification of bacteriophage lambda. J. Mol. Biol. 5:1836.
6. Arber, W.,, R. Yuan,, and T. A. Bickle. 1975. Strain-specific modification and restriction of DNA in bacteria. FEBS Proc. Symp. 9:322.
7. Bachi, B.,, J. Reiser,, and V. Pirrotta. 1979. Methylation and cleavage sequences of the EcoP1 restriction-modification enzyme. J. Mol. Biol. 128:143163.
8. Balbontin, R.,, G. Rowley,, M. G. Pucciarelli,, J. Lopez-Garrido,, Y. Wormstone,, S. Lucchini,, F. Garcia-Del Portillo,, J. C. Hinton,, and J. Casadesus. 2006. DNA adenine methylation regulates virulence gene expression in Salmonella enterica serovar Typhimurium. J. Bacteriol. 188:81608168.
9. Bayliss, C. D.,, M. J. Callaghan,, and E. R. Moxon. 2006. High allelic diversity in the methyltransferase gene of a phase variable type III restriction-modification system has implications for the fitness of Haemophilus influenzae. Nucleic Acids Res. 34:40464059.
10. Bayliss, C. D.,, D. Field,, and E. R. Moxon. 2001. The simple sequence contingency loci of Haemophilus influenzae and Neisseria meningitidis. J. Clin. Investig. 107:657662.
11. Bernarde, C.,, P. Lehours,, J. P. Lasserre,, M. Castroviejo,, M. Bonneu,, F. Megraud,, and A. Menard. 2010. Complexomics study of two Helicobacter pylori strains of two pathological origins: potential targets for vaccine development and new insight in bacteria metabolism. Mol. Cell. Proteomics 9:27962826.
12. Bickle, T. A.,, C. Brack,, and R. Yuan. 1978. ATP-induced conformational changes in the restriction endonuclease from Escherichia coli K-12. Proc. Natl. Acad. Sci. USA 75:30993103.
13. Bjorkholm, B. M.,, J. L. Guruge,, J. D. Oh,, A. J. Syder,, N. Salama,, K. Guillemin,, S. Falkow,, C. Nilsson,, P. G. Falk,, L. Engstrand,, and J. I. Gordon. 2002. 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. J. Biol. Chem. 277:3419134197.
14. Blomfield, I. C. 2001. The regulation of pap and type 1 fimbriation in Escherichia coli. Adv. Microb. Physiol. 45:149.
15. Blyn, L. B.,, B. A. Braaten,, and D. A. Low. 1990. Regulation of pap pilin phase variation by a mechanism involving differential Dam methylation states. EMBO J. 9:40454054.
16. Bourniquel, A. A.,, and T. A. Bickle. 2002. Complex restriction enzymes: NTP-driven molecular motors. Biochimie 84:10471059.
17. Boyer, H. W. 1971. DNA restrictions and modification mechanisms in bacteria. Annu. Rev. Microbiol. 25:153176.
18. Brocchi, M.,, A. Vasconcelos,, and A. Zaha. 2007. Restriction-modification systems in Mycoplasma spp. Genet. Mol. Biol. 30:236244.
19. Budroni, S.,, E. Siena,, J. C. Hotopp,, K. L. Seib,, D. Serruto,, C. Nofroni,, M. Comanducci,, D. R. Riley,, S. C. Daugherty,, S. V. Angiuoli,, A. Covacci,, M. Pizza,, R. Rappuoli,, E. R. Moxon,, H. Tettelin,, and D. Medini. 2011. Neisseria meningitidis is structured in clades associated with restriction modification systems that modulate homologous recombination. Proc. Natl. Acad. Sci. USA 108:44944499.
20. Buhler, R.,, and R. Yuan. 1978. Characterization of a restriction enzyme from Escherichia coli K carrying a mutation in the modification subunit. J. Biol. Chem. 253:67566760.
21. Campellone, K. G.,, A. J. Roe,, A. Lobner-Olesen,, K. C. Murphy,, L. Magoun,, M. J. Brady,, A. Donohue-Rolfe,, S. Tzipori,, D. L. Gally,, J. M. Leong,, and M. G. Marinus. 2007. Increased adherence and actin pedestal formation by dam-deficient enterohaemorrhagic Escherichia coli O157:H7. Mol. Microbiol. 63:14681481.
22. Casadesus, J.,, and D. Low. 2006. Epigenetic gene regulation in the bacterial world. Microbiol. Mol. Biol. Rev. 70:830856.
23. Chandler, M.,, and O. Fayet. 1993. Translational frameshifting in the control of transposition in bacteria. Mol. Microbiol. 7:497503.
24. Chatti, A.,, D. Daghfous,, and A. Landoulsi. 2008. Effect of repeated in vivo passage (in mice) on Salmonella typhimurium dam mutant virulence and fitness. Pathol. Biol. (Paris) 56:121124.
25. Chen, L.,, D. B. Paulsen,, D. W. Scruggs,, M. M. Banes,, B. Y. Reeks,, and M. L. Lawrence. 2003. Alteration of DNA adenine methylase (Dam) activity in Pasteurella multocida causes increased spontaneous mutation frequency and attenuation in mice. Microbiology 149:22832290.
26. Correnti, J.,, V. Munster,, T. Chan,, and M. Woude. 2002. Dam-dependent phase variation of Ag43 in Escherichia coli is altered in a seqA mutant. Mol. Microbiol. 44:521532.
27. Danese, P. N.,, L. A. Pratt,, S. L. Dove,, and R. Kolter. 2000. The outer membrane protein, antigen 43, mediates cell-to-cell interactions within Escherichia coli biofilms. Mol. Microbiol. 37:424432.
28. De Backer, O.,, and C. Colson. 1991. Transfer of the genes for the StyLTI restriction-modification system of Salmonella typhimurium to strains lacking modification ability results in death of the recipient cells and degradation of their DNA. J. Bacteriol. 173:13281330.
29. Donahue, J. P.,, D. A. Israel,, R. M. Peek,, M. J. Blaser,, and G. G. Miller. 2000. Overcoming the restriction barrier to plasmid transformation of Helicobacter pylori. Mol. Microbiol. 37:10661074.
30. Doronina, V. A.,, and N. E. Murray. 2001. The proteolytic control of restriction activity in Escherichia coli K-12. Mol. Microbiol. 39:416428.
31. Dryden, D. T.,, N. E. Murray,, and D. N. Rao. 2001. Nucleoside triphosphate-dependent restriction enzymes. Nucleic Acids Res. 29:37283741.
32. Dybvig, K. 1993. DNA rearrangements and phenotypic switching in prokaryotes. Mol. Microbiol. 10:465471.
33. Dybvig, K.,, R. Sitaraman,, and C. T. French. 1998. A family of phase-variable restriction enzymes with differing specificities generated by high-frequency gene rearrangements. Proc. Natl. Acad. Sci. USA 95:1392313928.
34. Eaton, K. A.,, S. Suerbaum,, C. Josenhans,, and S. Krakowka. 1996. Colonization of gnotobiotic piglets by Helicobacter pylori deficient in two flagellin genes. Infect. Immun. 64:24452448.
35. Falker, S.,, J. Schilling,, M. A. Schmidt,, and G. Heusipp. 2007. Overproduction of DNA adenine methyltransferase alters motility, invasion, and the lipopolysaccharide O-antigen composition of Yersinia enterocolitica. Infect. Immun. 75:49904997.
36. Fox, K. L.,, S. J. Dowideit,, A. L. Erwin,, Y. N. Srikhanta,, A. L. Smith,, and M. P. Jennings. 2007. Haemophilus influenzae phasevarions have evolved from type III DNA restriction systems into epigenetic regulators of gene expression. Nucleic Acids Res. 35:52425252.
37. Garcia-Del Portillo, F.,, M. G. Pucciarelli,, and J. Casadesus. 1999. DNA adenine methylase mutants of Salmonella typhimurium show defects in protein secretion, cell invasion, and M cell cytotoxicity. Proc. Natl. Acad. Sci. USA 96:1157811583.
38. Gewirtz, A. T.,, Y. Yu,, U. S. Krishna,, D. A. Israel,, S. L. Lyons,, and R. M. Peek, Jr. 2004. Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. J. Infect. Dis. 189:19141920.
39. Gibbs, C. P.,, B. Y. Reimann,, E. Schultz,, A. Kaufmann,, R. Haas,, and T. F. Meyer. 1989. Reassortment of pilin genes in Neisseria gonorrhoeae occurs by two distinct mechanisms. Nature 338:651652.
40. Gorbalenya, A. E.,, and E. V. Koonin. 1991. Endonuclease (R) subunits of type-I and type-III restriction-modification enzymes contain a helicase-like domain. FEBS Lett. 291:277281.
41. Gumulak-Smith, J.,, A. Teachman,, A. H. Tu,, J. W. Simecka,, J. R. Lindsey,, and K. Dybvig. 2001. Variations in the surface proteins and restriction enzyme systems of Mycoplasma pulmonis in the respiratory tract of infected rats. Mol. Microbiol. 40:10371044.
42. Haagmans, W.,, and M. van der Woude. 2000. Phase variation of Ag43 in Escherichia coli: Dam-dependent methylation abrogates OxyR binding and OxyR-mediated repression of transcription. Mol. Microbiol. 35:877887.
43. Hadi, S. M.,, B. Bachi,, S. Iida,, and T. A. Bickle. 1983. DNA restriction-modification enzymes of phage P1 and plasmid p15B. Subunit functions and structural homologies. J. Mol. Biol. 165:1934.
44. Hallet, B. 2001. Playing Dr Jekyll and Mr Hyde: combined mechanisms of phase variation in bacteria. Curr. Opin. Microbiol. 4:570581.
45. Hamilton, H. L.,, and J. P. Dillard. 2006. Natural transformation of Neisseria gonorrhoeae: from DNA donation to homologous recombination. Mol. Microbiol. 59:376385.
46. Hammerschmidt, S.,, R. Hilse,, J. P. van Putten,, R. Gerardy-Schahn,, A. Unkmeir,, and M. Frosch. 1996. Modulation of cell surface sialic acid expression in Neisseria meningitidis via a transposable genetic element. EMBO J. 15:192198.
47. Hartmann, E.,, and C. Lingwood. 1997. Brief heat shock treatment induces a long-lasting alteration in the glycolipid receptor binding specificity and growth rate of Haemophilus influenzae. Infect. Immun. 65:17291733.
48. Hartmann, E.,, C. A. Lingwood,, and J. Reidl. 2001. Heat-inducible surface stress protein (Hsp70) mediates sulfatide recognition of the respiratory pathogen Haemophilus influenzae. Infect. Immun. 69:34383441.
49. Heithoff, D. M.,, E. Y. Enioutina,, R. A. Daynes,, R. L. Sinsheimer,, D. A.Low, and M. J. Mahan. 2001. Salmonella DNA adenine methylase mutants confer cross-protective immunity. Infect. Immun. 69:67256730.
50. Heithoff, D. M.,, R. L. Sinsheimer,, D. A. Low,, and M. J. Mahan. 1999. An essential role for DNA adenine methylation in bacterial virulence. Science 284:967970.
51. Henderson, I. R.,, and P. Owen. 1999. The major phase-variable outer membrane protein of Escherichia coli structurally resembles the immunoglobulin A1 protease class of exported protein and is regulated by a novel mechanism involving Dam and OxyR. J. Bacteriol. 181:21322141.
52. Henderson, I. R.,, P. Owen,, and J. P. Nataro. 1999. Molecular switches—the ON and OFF of bacterial phase variation. Mol. Microbiol. 33:919932.
53. Herbert, M. A.,, S. Hayes,, M. E. Deadman,, C. M. Tang,, D. W. Hood,, and E. R. Moxon. 2002. Signature tagged mutagenesis of Haemophilus influenzae identifies genes required for in vivo survival. Microb. Pathog. 33:211223.
54. Hood, D. W.,, M. E. Deadman,, M. P. Jennings,, M. Bisercic,, R. D. Fleischmann,, J. C. Venter,, and E. R. Moxon. 1996. DNA repeats identify novel virulence genes in Haemophilus influenzae. Proc. Natl. Acad. Sci. USA 93:1112111125.
55. Humbelin, M.,, B. Suri,, D. N. Rao,, D. P. Hornby,, H. Eberle,, T. Pripfl,, S. Kenel,, and T. A. Bickle. 1988. 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. J. Mol. Biol. 200:2329.
56. Jakomin, M.,, D. Chessa,, A. J. Baumler,, and J. Casadesus. 2008. Regulation of the Salmonella enterica std fimbrial operon by DNA adenine methylation, SeqA, and HdfR. J. Bacteriol. 190:74067413.
57. Jennings, M. P.,, M. Virji,, D. Evans,, V. Foster,, Y. N. Srikhanta,, L. Steeghs,, P. van der Ley,, and E. R. Moxon. 1998. Identification of a novel gene involved in pilin glycosylation in Neisseria meningitidis. Mol. Microbiol. 29:975984.
58. Julio, S. M.,, D. M. Heithoff,, D. Provenzano,, K. E. Klose,, R. L. Sinsheimer,, D. A. Low,, and M. J. Mahan. 2001. DNA adenine methylase is essential for viability and plays a role in the pathogenesis of Yersinia pseudotuberculosis and Vibrio cholerae. Infect. Immun. 69:76107615.
59. Julio, S. M.,, D. M. Heithoff,, R. L. Sinsheimer,, D. A. Low,, and M. J. Mahan. 2002. DNA adenine methylase overproduction in Yersinia pseudotuberculosis alters YopE expression and secretion and host immune responses to infection. Infect. Immun. 70:10061009.
60. Kavermann, H.,, B. P. Burns,, K. Angermuller,, S. Odenbreit,, W. Fischer,, K. Melchers,, and R. Haas. 2003. Identification and characterization of Helicobacter pylori genes essential for gastric colonization. J. Exp. Med. 197:813822.
61. Kim, J. S.,, J. Li,, I. H. Barnes,, D. A. Baltzegar,, M. Pajaniappan,, T. W. Cullen,, M. S. Trent,, C. M. Burns,, and S. A. Thompson. 2008. Role of the Campylobacter jejuni Cj1461 DNA methyltransferase in regulating virulence characteristics. J. Bacteriol. 190:65246529.
62. Kong, H.,, L. F. Lin,, N. Porter,, S. Stickel,, D. Byrd,, J. Posfai,, and R. J. Roberts. 2000. Functional analysis of putative restriction-modification system genes in the Helicobacter pylori J99 genome. Nucleic Acids Res. 28:32163223.
63. Kutsukake, K.,, and T. Iino. 1980. Inversions of specific DNA segments in flagellar phase variation of Salmonella and inversion systems of bacteriophages P1 and Mu. Proc. Natl. Acad. Sci. USA 77:73387341.
64. Lee, S. K.,, A. Stack,, E. Katzowitsch,, S. I. Aizawa,, S. Suerbaum,, and C. Josenhans. 2003. Helicobacter pylori flagellins have very low intrinsic activity to stimulate human gastric epithelial cells via TLR5. Microbes Infect. 5:13451356.
65. Levinson, G.,, and G. A. Gutman. 1987. Slipped-strand mispairing: a major mechanism for DNA sequence evolution. Mol. Biol. Evol. 4:203221.
66. Lin, L. F.,, J. Posfai,, R. J. Roberts,, and H. Kong. 2001. Comparative genomics of the restriction-modification systems in Helicobacter pylori. Proc. Natl. Acad.Sci. USA 98:27402745.
67. Low, D. A.,, N. J. Weyand,, and M. J. Mahan. 2001. Roles of DNA adenine methylation in regulating bacterial gene expression and virulence. Infect. Immun. 69:71977204.
68. Makovets, S.,, V. A. Doronina,, and N. E. Murray. 1999. Regulation of endonuclease activity by proteolysis prevents breakage of unmodified bacterial chromosomes by type I restriction enzymes. Proc. Natl. Acad. Sci. USA 96:97579762.
69. Malone, T.,, R. M. Blumenthal,, and X. Cheng. 1995. Structure-guided analysis reveals nine sequence motifs conserved among DNA amino-methyltransferases, and suggests a catalytic mechanism for these enzymes. J. Mol. Biol. 253:618632.
70. Marinus, M. G.,, and J. Casadesus. 2009. Roles of DNA adenine methylation in host-pathogen interactions: mismatch repair, transcriptional regulation, and more. FEMS Microbiol. Rev. 33:488503.
71. Martin, P.,, K. Makepeace,, S. A. Hill,, D. W. Hood,, and E. R. Moxon. 2005. Microsatellite instability regulates transcription factor binding and gene expression. Proc. Natl. Acad. Sci. USA 102:38003804.
72. Mehling, J. S.,, H. Lavender,, and S. Clegg. 2007. A Dam methylation mutant of Klebsiella pneumoniae is partially attenuated. FEMS Microbiol. Lett. 268:187193.
73. Mehr, I. J.,, and H. S. Seifert. 1998. Differential roles of homologous recombination pathways in Neisseria gonorrhoeae pilin antigenic variation, DNA transformation and DNA repair. Mol. Microbiol. 30:697710.
74. Meisel, A.,, T. A. Bickle,, D. H. Kruger,, and C. Schroeder. 1992. Type III restriction enzymes need two inversely oriented recognition sites for DNA cleavage. Nature 355:467469.
75. Meisel, A.,, P. Mackeldanz,, T. A. Bickle,, D. H. Kruger,, and C. Schroeder. 1995. Type III restriction endonucleases translocate DNA in a reaction driven by recognition site-specific ATP hydrolysis. EMBO J. 14:29582966.
76. Moxon, E. R.,, P. B. Rainey,, M. A. Nowak,, and R. E. Lenski. 1994. Adaptive evolution of highly mutable loci in pathogenic bacteria. Curr. Biol. 4:2433.
77. Moxon, E. R.,, and D. S. Thaler. 1997. Microbial genetics. The tinkerer’s evolving tool-box. Nature 387:659, 661662.
78. Moxon, R.,, C. Bayliss,, and D. Hood. 2006. Bacterial contingency loci: the role of simple sequence DNA repeats in bacterial adaptation. Annu. Rev. Genet. 40:307333.
79. Murphy, K. C.,, J. M. Ritchie,, M. K. Waldor,, A. Lobner-Olesen,, and M. G. Marinus. 2008. Dam methyltransferase is required for stable lysogeny of the Shiga toxin (Stx2)-encoding bacteriophage 933W of enterohemorrhagic Escherichia coli O157:H7. J. Bacteriol. 190:438441.
80. Murray, N. E. 2000. Type I restriction systems: sophisticated molecular machines (a legacy of Bertani and Weigle). Microbiol. Mol. Biol. Rev. 64:412434.
81. Nicholson, B.,, and D. Low. 2000. DNA methylation-dependent regulation of pef expression in Salmonella typhimurium. Mol. Microbiol. 35:728742.
82. Nou, X.,, B. Braaten,, L. Kaltenbach,, and D. A. Low. 1995. Differential binding of Lrp to two sets of pap DNA binding sites mediated by Pap I regulates Pap phase variation in Escherichia coli. EMBO J. 14:57855797.
83. Peck, B.,, M. Ortkamp,, U. Nau,, M. Niederweis,, E. Hundt,, and B. Knapp. 2001. Characterization of four members of a multigene family encoding outer membrane proteins of Helicobacter pylori and their potential for vaccination. Microbes Infect. 3:171179.
84. Pettersson, A.,, T. Prinz,, A. Umar,, J. van der Biezen,, and J. Tommassen. 1998. Molecular characterization of LbpB, the second lactoferrin-binding protein of Neisseria meningitidis. Mol. Microbiol. 27:599610.
85. Pettersson, A.,, P. van der Ley,, J. T. Poolman,, and J. Tommassen. 1993. Molecular characterization of the 98-kilodalton iron-regulated outer membrane protein of Neisseria meningitidis. Infect. Immun. 61:47244733.
86. Pingoud, A.,, and A. Jeltsch. 1997. Recognition and cleavage of DNA by type-II restriction endonucleases. Eur. J. Biochem. 246:122.
87. Prieto, A. I.,, M. Jakomin,, I. Segura,, M. G. Pucciarelli,, F. Ramos-Morales,, F. Garcia-Del Portillo,, and J. Casadesus. 2007. The GATC-binding protein SeqA is required for bile resistance and virulence in Salmonella enterica serovar Typhimurium. J. Bacteriol. 189:84968502.
88. Pucciarelli, M. G.,, A. I. Prieto,, J. Casadesus,, and F. Garcia-del Portillo. 2002. Envelope instability in DNA adenine methylase mutants of Salmonella enterica. Microbiology 148:11711182.
89. Redaschi, N.,, and T. A. Bickle. 1996. Posttranscriptional regulation of EcoP1I and EcoP15I restriction activity. J. Mol. Biol. 257:790803.
90. Robertson, B. D.,, and T. F. Meyer. 1992. Genetic variation in pathogenic bacteria. Trends Genet. 8:422427.
91. Rocha, E. P.,, and A. Blanchard. 2002. Genomic repeats, genome plasticity and the dynamics of Mycoplasma evolution. Nucleic Acids Res. 30:20312042.
92. Saha, S.,, I. Ahmad,, Y. V. Reddy,, V. Krishnamurthy,, and D. N. Rao. 1998. Functional analysis of conserved motifs in type III restriction-modification enzymes. Biol. Chem. 379:511517.
93. Sarkari, J.,, N. Pandit,, E. R. Moxon,, and M. Achtman. 1994. Variable expression of the Opc outer membrane protein in Neisseria meningitidis is caused by size variation of a promoter containing poly-cytidine. Mol. Microbiol. 13:207217.
94. Saunders, N. J.,, A. C. Jeffries,, J. F. Peden,, D. W. Hood,, H. Tettelin,, R. Rappuoli,, and E. R. Moxon. 2000. Repeat-associated phase variable genes in the complete genome sequence of Neisseria meningitidis strain MC58. Mol. Microbiol. 37:207215.
95. Saunders, N. J.,, J. F. Peden,, D. W. Hood,, and E. R. Moxon. 1998. Simple sequence repeats in the Helicobacter pylori genome. Mol. Microbiol. 27:10911098.
96. Sears, A.,, L. J. Peakman,, G. G. Wilson,, and M. D. Szczelkun. 2005. Characterization of the type III restriction endonuclease PstII from Providencia stuartii. Nucleic Acids Res. 33:47754787.
97. Sears, A.,, and M. D. Szczelkun. 2005. Subunit assembly modulates the activities of the type III restriction-modification enzyme PstII in vitro. Nucleic Acids Res. 33:47884796.
98. Seib, K. L.,, I. R. Peak,, and M. P. Jennings. 2002. Phase variable restriction-modification systems in Moraxella catarrhalis. FEMS Immunol. Med. Microbiol. 32:159165.
99. Seib, K. L.,, E. Pigozzi,, A. Muzzi,, J. A. Gawthorne,, I. Delany,, M. P. Jennings,, and R. Rappuoli. 2011. A novel epigenetic regulator associated with the hypervirulent Neisseria meningitidis clonal complex 41/44. FASEB J. 25:36223633.
100. Seifert, H. S. 1996. Questions about gonococcal pilus phase- and antigenic variation. Mol. Microbiol. 21:433440.
101. Skoglund, A.,, B. Bjorkholm,, C. Nilsson,, A. Andersson,, C. Jernberg,, K. Schirwitz,, C. Enroth,, M. Krabbe,, and L. Engstrand. 2007. Functional analysis of the M.HpyAIV DNA methyltransferase of Helicobacter pylori. J. Bacteriol. 189:89148921.
102. Srikhanta, Y. N.,, S. J. Dowideit,, J. L. Edwards,, M. L. Falsetta,, H. J. Wu,, O. B. Harrison,, K. L. Fox,, K. L. Seib,, T. L. Maguire,, A. H. Wang,, M. C. Maiden,, S. M. Grimmond,, M. A. Apicella,, and M. P. Jennings. 2009. Phasevarions mediate random switching of gene expression in pathogenic Neisseria. PLoS Pathog. 5:e1000400.
103. Srikhanta, Y. N.,, K. L. Fox,, and M. P. Jennings. 2010. The phasevarion: phase variation of type III DNA methyltransferases controls coordinated switching in multiple genes. Nat. Rev. Microbiol. 8:196206.
104. Srikhanta, Y. N.,, R. G. Gorrell,, J. A. Steen,, J. A. Gawthorne,, T. Kwok,, S. M. Grimmond,, R. M. Robins-Browne,, and M. P. Jennings. 2011. Phasevarion mediated epigenetic gene regulation in Helicobacter pylori. PLoS One 6:e27569.
105. Srikhanta, Y. N.,, T. L. Maguire,, K. J. Stacey,, S. M. Grimmond,, and M. P. Jennings. 2005. The phasevarion: a genetic system controlling coordinated, random switching of expression of multiple genes. Proc. Natl. Acad. Sci. USA 102:55475551.
106. Stibitz, S.,, W. Aaronson,, D. Monack,, and S. Falkow. 1989. Phase variation in Bordetella pertussis by frameshift mutation in a gene for a novel two-component system. Nature 338:266269.
107. Taylor, V. L.,, R. W. Titball,, and P. C. Oyston. 2005. Oral immunization with a dam mutant of Yersinia pseudotuberculosis protects against plague. Microbiology 151:19191926.
108. van Belkum, A.,, S. Scherer,, L. van Alphen,, and H. Verbrugh. 1998. Short-sequence DNA repeats in prokaryotic genomes. Microbiol. Mol. Biol. Rev. 62:275293.
109. van der Woude, M.,, B. Braaten,, and D. Low. 1996. Epigenetic phase variation of the pap operon in Escherichia coli. Trends Microbiol. 4:59.
110. van der Woude, M. W. 2006. Re-examining the role and random nature of phase variation. FEMS Microbiol. Lett. 254:190197.
111. van der Woude, M. W.,, and A. J. Baumler. 2004. Phase and antigenic variation in bacteria. Clin. Microbiol. Rev. 17:581611.
112. van Ham, S. M.,, L. van Alphen,, F. R. Mooi,, and J. P. van Putten. 1993. Phase variation of Haemophilus influenzae fimbriae: transcriptional control of two divergent genes through a variable combined promoter region. Cell 73:11871196.
113. Vitkute, J.,, K. Stankevicius,, G. Tamulaitiene,, Z. Maneliene,, A. Timinskas,, D. E. Berg,, and A. Janulaitis. 2001. Specificities of eleven different DNA methyltransferases of Helicobacter pylori strain 26695. J. Bacteriol. 183:443450.
114. Wallecha, A.,, V. Munster,, J. Correnti,, T. Chan,, and M. van der Woude. 2002. Dam- and OxyR-dependent phase variation of agn43: essential elements and evidence for a new role of DNA methylation. J. Bacteriol. 184:33383347.
115. Weiser, J. N.,, A. Williams,, and E. R. Moxon. 1990. Phase-variable lipopolysaccharide structures enhance the invasive capacity of Haemophilus influenzae. Infect. Immun. 58:34553457.
116. Weyand, N. J.,, and D. A. Low. 2000. Regulation of Pap phase variation. Lrp is sufficient for the establishment of the phase off pap DNA methylation pattern and repression of pap transcription in vitro. J. Biol. Chem. 275:31923200.
117. Willcock, D. F.,, D. T. Dryden,, and N. E. Murray. 1994. A mutational analysis of the two motifs common to adenine methyltransferases. EMBO J. 13:39023908.
118. Wion, D.,, and J. Casadesus. 2006. N6-methyl-adenine: an epigenetic signal for DNA-protein interactions. Nat. Rev. Microbiol. 4:183192.


Generic image for table
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

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error