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dc.contributor.authorShell, Scarlet S.
dc.contributor.authorBaek, Seung-Hun
dc.contributor.authorShah, Rupal R.
dc.contributor.authorSassetti, Christopher M.
dc.contributor.authorDedon, Peter C.
dc.contributor.authorFortune, Sarah M.
dc.contributor.authorPrestwich, Erin
dc.date.accessioned2013-09-30T14:57:48Z
dc.date.available2013-09-30T14:57:48Z
dc.date.issued2013-07
dc.date.submitted2012-07
dc.identifier.issn1553-7374
dc.identifier.issn1553-7366
dc.identifier.urihttp://hdl.handle.net/1721.1/81235
dc.description.abstractDNA methylation regulates gene expression in many organisms. In eukaryotes, DNA methylation is associated with gene repression, while it exerts both activating and repressive effects in the Proteobacteria through largely locus-specific mechanisms. Here, we identify a critical DNA methyltransferase in M. tuberculosis, which we term MamA. MamA creates N[superscript 6]-methyladenine in a six base pair recognition sequence present in approximately 2,000 copies on each strand of the genome. Loss of MamA reduces the expression of a number of genes. Each has a MamA site located at a conserved position relative to the sigma factor −10 binding site and transcriptional start site, suggesting that MamA modulates their expression through a shared, not locus-specific, mechanism. While strains lacking MamA grow normally in vitro, they are attenuated in hypoxic conditions, suggesting that methylation promotes survival in discrete host microenvironments. Interestingly, we demonstrate strikingly different patterns of DNA methyltransferase activity in different lineages of M. tuberculosis, which have been associated with preferences for distinct host environments and different disease courses in humans. Thus, MamA is the major functional adenine methyltransferase in M. tuberculosis strains of the Euro-American lineage while strains of the Beijing lineage harbor a point mutation that largely inactivates MamA but possess a second functional DNA methyltransferase. Our results indicate that MamA influences gene expression in M. tuberculosis and plays an important but strain-specific role in fitness during hypoxia.en_US
dc.description.sponsorshipNational Institute of Environmental Health Sciences (Training Grant in Environmental Toxicology Award (5T32-ES007020-34)en_US
dc.description.sponsorshipSingapore-MIT Alliance for Research and Technologyen_US
dc.language.isoen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1371/journal.ppat.1003419en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by/2.5/en_US
dc.sourcePLoSen_US
dc.titleDNA Methylation Impacts Gene Expression and Ensures Hypoxic Survival of Mycobacterium tuberculosisen_US
dc.typeArticleen_US
dc.identifier.citationShell, Scarlet S., Erin G. Prestwich, Seung-Hun Baek, Rupal R. Shah, Christopher M. Sassetti, Peter C. Dedon, and Sarah M. Fortune. “DNA Methylation Impacts Gene Expression and Ensures Hypoxic Survival of Mycobacterium tuberculosis.” Edited by William R. Bishai. PLoS Pathogens 9, no. 7 (July 4, 2013): e1003419.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.mitauthorPrestwich, Erinen_US
dc.contributor.mitauthorDedon, Peter C.en_US
dc.relation.journalPLoS Pathogensen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsShell, Scarlet S.; Prestwich, Erin G.; Baek, Seung-Hun; Shah, Rupal R.; Sassetti, Christopher M.; Dedon, Peter C.; Fortune, Sarah M.en_US
dc.identifier.orcidhttps://orcid.org/0000-0003-0011-3067
mit.licensePUBLISHER_CCen_US


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