Open AccessEpigenomic characterization of Clostridioides difficile finds a conserved DNA methyltransferase that mediates sporulation and pathogenesis
Author(s) -
Pedro H. Oliveira,
John W. Ribis,
Elizabeth M. Garrett,
Dominika Trzilova,
Alex Kim,
Ognjen Sekulović,
Edward A. Mead,
Theodore R. Pak,
Shaohua 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 Kashif Bashir,
Gopi Patel,
Frances Wallach,
Camille Hamula,
Shirish Huprikar,
Eric E. Schadt,
Robert Sebra,
Harm van Bakel,
Andrew Kasarskis,
Rita Tamayo,
Aimee Shen,
Gang Fang
Publication year - 2019
Publication title -
nature microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.305
H-Index - 79
ISSN - 2058-5276
DOI - 10.1038/s41564-019-0613-4
Subject(s) - epigenomics , epigenome , biology , dna methylation , epigenetics , transcriptome , dna methyltransferase , genetics , methyltransferase , genome , microbiome , computational biology , gene , methylation , gene expression
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.