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Nat Microbiol. 2019 Nov 25. doi: 10.1038/s41564-019-0613-4. [Epub ahead of print]

Epigenomic characterization of Clostridioides difficile finds a conserved DNA methyltransferase that mediates sporulation and pathogenesis.

Author information

1
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, NY, USA.
2
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA.
3
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
4
Microbial Evolutionary Genomics, Institut Pasteur, Paris, France.
5
CNRS, UMR3525, Paris, France.
6
Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY, USA.
7
Department of Pharmacological Sciences and Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY, USA.
8
Sema4, Stamford, CT, USA.
9
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA. aimee.shen@tufts.edu.
10
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, NY, USA. gang.fang@mssm.edu.

Abstract

Clostridioides (formerly Clostridium) difficile is a leading cause of healthcare-associated infections. Although considerable progress has been made in the understanding of its genome, the epigenome of C. difficile and its functional impact has not been systematically explored. Here, we perform a comprehensive DNA methylome analysis of C. difficile using 36 human isolates and observe a high level of epigenomic diversity. We discovered an orphan DNA methyltransferase with a well-defined specificity, the corresponding gene of which is highly conserved across our dataset and in all of the approximately 300 global C. difficile genomes examined. Inactivation of the methyltransferase gene negatively impacts sporulation, a key step in C. difficile disease transmission, and these results are consistently supported by multiomics data, genetic experiments and a mouse colonization model. Further experimental and transcriptomic analyses suggest that epigenetic regulation is associated with cell length, biofilm formation and host colonization. These findings provide a unique epigenetic dimension to characterize medically relevant biological processes in this important pathogen. This study also provides a set of methods for comparative epigenomics and integrative analysis, which we expect to be broadly applicable to bacterial epigenomic studies.

PMID:
31768029
DOI:
10.1038/s41564-019-0613-4

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