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Epigenomic and functional characterization of a core DNA methyltransferase in the human pathogen Clostridium difficile

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, Colleen Beckford, Nathalie E. Zeitouni, Deena Altman, Elizabeth Webster, Irina Oussenko, Supinda Bunyavanich, Aneel K. Aggarwal, Ali Bashir, Gopi Patel, Camille Hamula, Shirish Huprikar, Eric E. Schadt, Robert Sebra, View ORCID ProfileHarm van Bakel, Andrew Kasarskis, Rita Tamayo, Aimee Shen, Gang Fang
doi: https://doi.org/10.1101/398891
Pedro H. Oliveira
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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John W. Ribis
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
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Elizabeth M. Garrett
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
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Dominika Trzilova
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
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Alex Kim
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Ognjen Sekulovic
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
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Edward A. Mead
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Theodore Pak
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Shijia Zhu
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Gintaras Deikus
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Marie Touchon
Microbial Evolutionary Genomics, Institut Pasteur, 25–28 rue du Docteur Roux, Paris, 75015, FranceCNRS, UMR3525, 25–28 rue du Docteur Roux, Paris, 75015, France
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Colleen Beckford
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Nathalie E. Zeitouni
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Deena Altman
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of AmericaDepartment of Medicine, Infectious Disease, Mount Sinai School of Medicine, New York, New York, United States of America
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Elizabeth Webster
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Irina Oussenko
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Supinda Bunyavanich
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Aneel K. Aggarwal
Department of Pharmacological Sciences and Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York, United States of America
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Ali Bashir
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Gopi Patel
Department of Medicine, Infectious Disease, Mount Sinai School of Medicine, New York, New York, United States of America
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Camille Hamula
Department of Medicine, Infectious Disease, Mount Sinai School of Medicine, New York, New York, United States of America
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Shirish Huprikar
Department of Medicine, Infectious Disease, Mount Sinai School of Medicine, New York, New York, United States of America
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Eric E. Schadt
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Robert Sebra
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Harm van Bakel
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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  • ORCID record for Harm van Bakel
Andrew Kasarskis
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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Rita Tamayo
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
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Aimee Shen
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
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  • For correspondence: aimee.shen@tufts.edu gang.fang@mssm.edu
Gang Fang
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York, United States of America
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  • For correspondence: aimee.shen@tufts.edu gang.fang@mssm.edu
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Abstract

Clostridioides difficile is a leading cause of health care-associated infections. Although significant 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 performed the first comprehensive DNA methylome analysis of C. difficile using 36 human isolates and observed great epigenomic diversity. We discovered an orphan DNA methyltransferase with a well-defined specificity whose corresponding gene is highly conserved across our dataset and in all ~300 global C. difficile genomes examined. Inactivation of the methyltransferase gene negatively impacted sporulation, a key step in C. difficile disease transmission, consistently supported by multi-omics data, genetic experiments, and a mouse colonization model. Further experimental and transcriptomic analysis also suggested that epigenetic regulation is associated with cell length, biofilm formation, and host colonization. These findings open up a new epigenetic dimension to characterize medically relevant biological processes in this critical pathogen. This work also provides a set of methods for comparative epigenomics and integrative analysis, which we expect to be broadly applicable to bacterial epigenomics studies.

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Posted July 23, 2019.
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Epigenomic and functional characterization of a core DNA methyltransferase in the human pathogen Clostridium difficile
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, Colleen Beckford, Nathalie E. Zeitouni, Deena Altman, Elizabeth Webster, Irina Oussenko, Supinda Bunyavanich, Aneel K. Aggarwal, Ali Bashir, Gopi Patel, Camille Hamula, Shirish Huprikar, Eric E. Schadt, Robert Sebra, Harm van Bakel, Andrew Kasarskis, Rita Tamayo, Aimee Shen, Gang Fang
bioRxiv 398891; doi: https://doi.org/10.1101/398891
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Epigenomic and functional characterization of a core DNA methyltransferase in the human pathogen Clostridium difficile
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, Colleen Beckford, Nathalie E. Zeitouni, Deena Altman, Elizabeth Webster, Irina Oussenko, Supinda Bunyavanich, Aneel K. Aggarwal, Ali Bashir, Gopi Patel, Camille Hamula, Shirish Huprikar, Eric E. Schadt, Robert Sebra, Harm van Bakel, Andrew Kasarskis, Rita Tamayo, Aimee Shen, Gang Fang
bioRxiv 398891; doi: https://doi.org/10.1101/398891

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