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

Pedro H. Oliveira, John W. Ribis, Elizabeth M. Garrett, Dominika Trzilova, Alex Kim, Ognjen Sekulovic, Edward A. Mead, Theodore Pak, Shijia Zhu, Gintaras Deikus, Marie Touchon, Martha Lewis-Sandari, Colleen Beckford, Nathalie E. Zeitouni, Deena R. Altman, Elizabeth Webster, Irina Oussenko, Supinda Bunyavanich, Aneel K. Aggarwal, Ali BashirGopi Patel, Frances Wallach, Camille Hamula, Shirish Huprikar, Eric E. Schadt, Robert Sebra, Harm van Bakel, Andrew Kasarskis, Rita Tamayo, Aimee Shen, Gang Fang

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)166-180
Number of pages15
JournalNature Microbiology
Issue number1
StatePublished - Jan 1 2020

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology


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