Intracellular growth of Chlamydia trachomatis leads to global histone hypermethylation by impairing demethylation
- Institut Pasteur, France
- Duke University, United States
- Université Paris Cité, France
- Barcelona Institute for Science and Technology, Spain
- Institut Pasteur, CNRS UMR6047, France
- Institut de Recerca Biomèdica, Spain
- UT Southwestern Medical Center, United States
Abstract
Chlamydia trachomatis, an intracellular bacterium, highjacks metabolites from the host cell for its own proliferation. We provide evidence of global hypermethylation of the host proteome, including histones, during the late stages of infection. Single cell analyses revealed co-occurrence of several methylated residues on histones, while infection did not alter S-adenosyl methionine levels. Histone hypermethylation correlated positively with bacterial load and was prevented by antibiotic treatment. Mapping of trimethylation of histone 3 at residues K4 and K9 revealed a broad distribution throughout chromatin. Nuclear fractions of infected cells exhibited a fourfold decrease of demethylase activity against H3K4me3 and a twofold increase in succinate concentration, a competitive inhibitor for the demethylase co-factor a-ketoglutarate. Supplementation of the culture medium with dimethyl-ketoglutarate (DMKG) or with iron, a second co-factor of histone lysine demethylases, reduced histone hypermethylation. DMKG supplementation modified the transcription of about one third of the infection-responsive genes, indicating that histone hypermethylation contributes to modulating the transcriptional response of the host to infection. Finally, chemical inhibition of histone demethylases in a mouse model of infection showed a moderate benefit regarding the outcome of infection. Overall, our data show that the metabolic pressure exerted by a pathogen with an intracellular lifestyle drives epigenetic changes in infected cells.
Data availability
Microarray data and ChIP-seq data have been deposited in GEO under accession codes GSE265791 and GSE265792 respectively.The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD051857.
Article and author information
Author details
Quentin Giai Gianetto
Elisabeth D Martinez
Funding
Agence Nationale de la Recherche (20-PAMR-0011 TheraEPI)
- Chloé I Charendorff
- Félix V Louchez
- Yongzheng Wu
- Laure Blanchet
- Magalie Duchateau
- Quentin Giai Gianetto
- Mariette Matondo
- Frédéric Bonhomme
- Agathe Subtil
Institut National Du Cancer (INCA_16719)
- Chloé I Charendorff
- Félix V Louchez
- Yongzheng Wu
- Guillaume Velasco
- Laure Blanchet
- Laurence Del Maestro
- Slimane Ait-Si-Ali
- Agathe Subtil
Fondation ARC pour la Recherche sur le Cancer
- Chloé I Charendorff
- Agathe Subtil
Welch Foundation (I-1878)
- Elisabeth D Martinez
Centre National de la Recherche Scientifique
- Stéphanie Perrinet
- Laure Blanchet
- Laurence Del Maestro
- Slimane Ait-Si-Ali
- Frédéric Bonhomme
- Agathe Subtil
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The experiments were performed in accordance with the French national and European laws regarding the protection of animals used for experimental and other scientific purposes. The study was approved by the ethics committee of Institut Pasteur (approval N{degree sign}dap210086). Every effort was made to minimize suffering.
Human subjects: Primary epithelial cells were isolated from ectocervix biopsies of female patients after approval by the French Ethical Committee 'CPP Ile de France 1' on May 9, 2016. Approval and authorization of the National Data Protection authority ('Commission Nationale de l'Informatique et des Libertés', CNIL) have been obtained for the research protocol, in compliance with the Helsinki principles.
Copyright
© 2026, Charendorff et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 0
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Intracellular growth of Chlamydia trachomatis leads to global histone hypermethylation by impairing demethylation
eLife 15:e110111.
https://doi.org/10.7554/eLife.110111
