4-Methylcytosine DNA modification is critical for global epigenetic regulation and virulence in the human pathogen Leptospira interrogans

Autor: Céline Lorioux, Robert A. Gaultney, Jean-Yves Coppée, Charlotte Cockram, Odile Sismeiro, Rachel Legendre, Frédéric J. Veyrier, Mathieu Picardeau, Hugo Varet, Antony T. Vincent
Přispěvatelé: Biologie des Spirochètes / Biology of Spirochetes, Institut Pasteur [Paris], Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Pôle Biomics (C2RT), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Régulation spatiale des Génomes - Spatial Regulation of Genomes, Institut Pasteur [PTR 30-2017 to M.P.], ANR 18 CE15 0027 LEPTOMOVE to M.P., Pasteur Foundation Fellowship to R.A.G. (April 2017–June 2020), ERC grant agreement 771813 to R.K., Fellowship from the Natural Sciences and Engineering Research Council of Canada to ATV. FJV is a research scholar of the Fonds de Recherche du Québec-Santé. Funding for open access charge: Institut Pasteur., We thank Drs. Matsunaga and Haake for providing plasmid pRAT724 and Dr. Koszul for feedback on CCMs. We thank Dr. Linda Grillova for aid with bioinformatic analysis and critical reading of the manuscript. We also thank Drs. Simonetta Gribaldo and Nadia Benaroudj for critical reading of the manuscript., ANR-18-CE15-0027,LEPTOMOVE,Mécanismes moléculaires de la motilité chez les spirochètes: le modèle de l'endoflagelle des leptospires(2018), Institut Pasteur [Paris] (IP), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Nucleic Acids Research
Nucleic Acids Research, Oxford University Press, 2020, pp.gkaa966. ⟨10.1093/nar/gkaa966⟩
Nucleic Acids Research, 2020, pp.gkaa966. ⟨10.1093/nar/gkaa966⟩
ISSN: 0305-1048
1362-4962
Popis: In bacteria, DNA methylation can be facilitated by ‘orphan’ DNA methyltransferases lacking cognate restriction endonucleases, but whether and how these enzymes control key cellular processes are poorly understood. The effects of a specific modification, 4-methylcytosine (4mC), are even less clear, as this epigenetic marker is unique to bacteria and archaea, whereas the bulk of epigenetic research is currently performed on eukaryotes. Here, we characterize a 4mC methyltransferase from the understudied pathogen Leptospira spp. Inactivating this enzyme resulted in complete abrogation of CTAG motif methylation, leading to genome-wide dysregulation of gene expression. Mutants exhibited growth defects, decreased adhesion to host cells, higher susceptibility to LPS-targeting antibiotics, and, importantly, were no longer virulent in an acute infection model. Further investigation resulted in the discovery of at least one gene, that of an ECF sigma factor, whose transcription was altered in the methylase mutant and, subsequently, by mutation of the CTAG motifs in the promoter of the gene. The genes that comprise the regulon of this sigma factor were, accordingly, dysregulated in the methylase mutant and in a strain overexpressing the sigma factor. Our results highlight the importance of 4mC in Leptospira physiology, and suggest the same of other understudied species.
Databáze: OpenAIRE
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