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FASEB J. 2014 Dec;28(12):5197-207. doi: 10.1096/fj.14-256578. Epub 2014 Sep 2.

ModM DNA methyltransferase methylome analysis reveals a potential role for Moraxella catarrhalis phasevarions in otitis media.

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Institute for Glycomics and.
Pacific Biosciences, Menlo Park, California, USA; and.
Center for Microbial Pathogenesis, Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
Institute for Glycomics and School of Medical Science, Griffith University, Southport, Queensland, Australia;
Institute for Glycomics and


Moraxella catarrhalis is a significant cause of otitis media and exacerbations of chronic obstructive pulmonary disease. Here, we characterize a phase-variable DNA methyltransferase (ModM), which contains 5'-CAAC-3' repeats in its open reading frame that mediate high-frequency mutation resulting in reversible on/off switching of ModM expression. Three modM alleles have been identified (modM1-3), with modM2 being the most commonly found allele. Using single-molecule, real-time (SMRT) genome sequencing and methylome analysis, we have determined that the ModM2 methylation target is 5'-GAR(m6)AC-3', and 100% of these sites are methylated in the genome of the M. catarrhalis 25239 ModM2 on strain. Proteomic analysis of ModM2 on and off variants revealed that ModM2 regulates expression of multiple genes that have potential roles in colonization, infection, and protection against host defenses. Investigation of the distribution of modM alleles in a panel of M. catarrhalis strains, isolated from the nasopharynx of healthy children or middle ear effusions from patients with otitis media, revealed a statistically significant association of modM3 with otitis media isolates. The modulation of gene expression via the ModM phase-variable regulon (phasevarion), and the significant association of the modM3 allele with otitis media, suggests a key role for ModM phasevarions in the pathogenesis of this organism.


SMRT; epigenetic regulation; middle ear infection; phase variation; single-molecule, real-time genome sequencing

[Indexed for MEDLINE]

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