Epigenomic characterization of Clostridioides difficile finds a conserved DNA methyltransferase that mediates sporulation and pathogenesis
- 25 November 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Microbiology
- Vol. 5 (1), 166-180
- https://doi.org/10.1038/s41564-019-0613-4
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.Keywords
This publication has 115 references indexed in Scilit:
- Fast gapped-read alignment with Bowtie 2Nature Methods, 2012
- The variant call format and VCFtoolsBioinformatics, 2011
- Direct detection of DNA methylation during single-molecule, real-time sequencingNature Methods, 2010
- BEDTools: a flexible suite of utilities for comparing genomic featuresBioinformatics, 2010
- Reordering contigs of draft genomes using the Mauve AlignerBioinformatics, 2009
- The Sequence Alignment/Map format and SAMtoolsBioinformatics, 2009
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- Phage_Finder: Automated identification and classification of prophage regions in complete bacterial genome sequencesNucleic Acids Research, 2006
- The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genomeNature Genetics, 2006
- Blast2GO: a universal tool for annotation, visualization and analysis in functional genomics researchBioinformatics, 2005