Phosphorothioate DNA modification by BREX type 4 systems in the human gut microbiome

Among dozens of microbial DNA modifications regulating gene expression and host defense, phosphorothioation (PT) is the only known backbone modification, with sulfur inserted at a non-bridging oxygen by dnd and ssp gene families. Here we explored the distribution of PT genes in 13,663 human gut microbiome genomes, finding that 6.3% possessed dnd or ssp genes predominantly in Bacillota, Bacteroidota, and Pseudomonadota. This analysis revealed several previously undescribed PT synthesis systems, including type 4 Bacteriophage Exclusion (BREX) type 4 brx genes, which we genetically validated in Bacteroides salyersiae. Mass spectrometric analysis of DNA from 226 gut microbiome isolates possessing dnd, ssp, and brx genes revealed 8 PT dinucleotide settings confirmed in 10 consensus sequences by PT-specific DNA sequencing. Genomic analysis showed PT enrichment in rRNA genes and depletion at gene boundaries. These results illustrate the power of the microbiome for discovering prokaryotic epigenetics and the widespread distribution of oxidation-sensitive PTs in gut microbes.

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Publication Details

Journal
Nature Communications
Published
2026-01-22
DOI
https://doi.org/10.1038/s41467-026-68412-5
Primary Topic
Metalloenzymes and iron-sulfur proteins
Type
article
Field-Weighted Citation Impact
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article

Phosphorothioate DNA modification by BREX type 4 systems in the human gut microbiome

Michael S. DeMott, Catherine Girard, Yvonne Ayerki Nartey, Lewis R. Roberts et al.
Nature Communications
Metalloenzymes and iron-sulfur proteins
article

Phosphorothioate DNA modification by BREX type 4 systems in the human gut microbiome

Michael S. DeMott, Catherine Girard, Yvonne Ayerki Nartey, Lewis R. Roberts, J. Alm Eric, Le Thanh Tu Nguyen, Dedon Peter C., Jenni Lehtimäki, Ivan Emil Mwikarago, Audax Z. P. Mabulla, K. Flores, Mathieu Groussin, Brittany Berdy, Laurie E Comstock, B Jesse Shapiro, Charles A Onyekwere, Shane R Byrne, John Rusine Bahunde, Mathilde Poyet, Yifeng Yuan
article en

Abstract

Among dozens of microbial DNA modifications regulating gene expression and host defense, phosphorothioation (PT) is the only known backbone modification, with sulfur inserted at a non-bridging oxygen by dnd and ssp gene families. Here we explored the distribution of PT genes in 13,663 human gut microbiome genomes, finding that 6.3% possessed dnd or ssp genes predominantly in Bacillota, Bacteroidota, and Pseudomonadota. This analysis revealed several previously undescribed PT synthesis systems, including type 4 Bacteriophage Exclusion (BREX) type 4 brx genes, which we genetically validated in Bacteroides salyersiae. Mass spectrometric analysis of DNA from 226 gut microbiome isolates possessing dnd, ssp, and brx genes revealed 8 PT dinucleotide settings confirmed in 10 consensus sequences by PT-specific DNA sequencing. Genomic analysis showed PT enrichment in rRNA genes and depletion at gene boundaries. These results illustrate the power of the microbiome for discovering prokaryotic epigenetics and the widespread distribution of oxidation-sensitive PTs in gut microbes.

Nature CommunicationsVol. 17(1)
Université du Québec à Chicoutimi (CA), Broad Institute (US), Lagos State University (NG), Mayo Clinic (US), University of Helsinki (FI), University of Cape Coast (GH), University of Auckland (NZ), MGH Institute of Health Professions (US), University of Dar es Salaam (TZ), Finnish Environment Institute (FI), United States Pharmacopeial Convention (US), Center for Environmental Health (US), University of Kigali (RW), Hochschule für Angewandte Wissenschaften Kiel (DE), Christian-Albrechts-Universität zu Kiel (DE), University of Chicago (US), University of Rwanda (RW), Duchossois Group (United States) (US), Harvard–MIT Division of Health Sciences and Technology (US), Wisdom Health (United States) (US), McGill Genome Centre (CA), Community Options (United States) (US), Rwanda Biomedical Center (RW), Food and Drug Administration (TH), Clinical Research Center Kiel (DE), Singapore-MIT Alliance for Research and Technology (SG), Université Laval (CA), McGill University (CA), Massachusetts Institute of Technology (US)
Openalex Percentile: Top 81%
Metalloenzymes and iron-sulfur proteins
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