DNA Methylation Impacts Gene Expression and Ensures Hypoxic Survival of Mycobacterium tuberculosis
DNA 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 i...
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2013
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| Online Access: | http://hdl.handle.net/1721.1/81235 https://orcid.org/0000-0003-0011-3067 |
| _version_ | 1826202180788420608 |
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| author | Shell, Scarlet S. Baek, Seung-Hun Shah, Rupal R. Sassetti, Christopher M. Dedon, Peter C. Fortune, Sarah M. Prestwich, Erin |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Shell, Scarlet S. Baek, Seung-Hun Shah, Rupal R. Sassetti, Christopher M. Dedon, Peter C. Fortune, Sarah M. Prestwich, Erin |
| author_sort | Shell, Scarlet S. |
| collection | MIT |
| description | DNA 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. |
| first_indexed | 2024-09-23T12:03:28Z |
| format | Article |
| id | mit-1721.1/81235 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:03:28Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/812352022-10-01T07:52:27Z DNA Methylation Impacts Gene Expression and Ensures Hypoxic Survival of Mycobacterium tuberculosis Shell, Scarlet S. Baek, Seung-Hun Shah, Rupal R. Sassetti, Christopher M. Dedon, Peter C. Fortune, Sarah M. Prestwich, Erin Massachusetts Institute of Technology. Department of Biological Engineering Prestwich, Erin Dedon, Peter C. DNA 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. National Institute of Environmental Health Sciences (Training Grant in Environmental Toxicology Award (5T32-ES007020-34) Singapore-MIT Alliance for Research and Technology 2013-09-30T14:57:48Z 2013-09-30T14:57:48Z 2013-07 2012-07 Article http://purl.org/eprint/type/JournalArticle 1553-7374 1553-7366 http://hdl.handle.net/1721.1/81235 Shell, 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. https://orcid.org/0000-0003-0011-3067 en_US http://dx.doi.org/10.1371/journal.ppat.1003419 PLoS Pathogens Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Shell, Scarlet S. Baek, Seung-Hun Shah, Rupal R. Sassetti, Christopher M. Dedon, Peter C. Fortune, Sarah M. Prestwich, Erin DNA Methylation Impacts Gene Expression and Ensures Hypoxic Survival of Mycobacterium tuberculosis |
| title | DNA Methylation Impacts Gene Expression and Ensures Hypoxic Survival of Mycobacterium tuberculosis |
| title_full | DNA Methylation Impacts Gene Expression and Ensures Hypoxic Survival of Mycobacterium tuberculosis |
| title_fullStr | DNA Methylation Impacts Gene Expression and Ensures Hypoxic Survival of Mycobacterium tuberculosis |
| title_full_unstemmed | DNA Methylation Impacts Gene Expression and Ensures Hypoxic Survival of Mycobacterium tuberculosis |
| title_short | DNA Methylation Impacts Gene Expression and Ensures Hypoxic Survival of Mycobacterium tuberculosis |
| title_sort | dna methylation impacts gene expression and ensures hypoxic survival of mycobacterium tuberculosis |
| url | http://hdl.handle.net/1721.1/81235 https://orcid.org/0000-0003-0011-3067 |
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