DNA Methylation Impacts Gene Expression and Ensures Hypoxic Survival of Mycobacterium tuberculosis

PLoS Pathogens

Peter C. Dedon¹  Erin G. Prestwich¹  Scarlet S. Shell²  Sarah M. Fortune²  Rupal R. Shah²  Christopher M. Sassetti³  Seung-Hun Baek³ 

[1] Department of Biological Engineering and Center for Environmental Health Studies, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America;Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America;Department of Microbiology & Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America

关键词: DNA methylation;    Mycobacterium tuberculosis;    Gene expression;    Methylation;    Sequence motif analysis;    Gene regulation;    Methyltransferases;    Adenine;   

DOI  :  10.1371/journal.ppat.1003419

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 N6-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.

【 授权许可】

CC BY