The Helicobacter pylori orphan ATTAAT-specific methyltransferase M.Hpy99XIX plays a central role in the coordinated regulation of genes involved in iron metabolism
ABSTRACT Helicobacter pylori genomes contain a large and variable portfolio of methyltransferases (MTases), creating a highly diverse methylome. Here, we characterize a highly conserved ATTAAT-specific MTase, M.Hpy99XIX (H. pylori strain J99, alternative designations in other strains, M.HpyAVII and...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2025-07-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01209-25 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850100461079625728 |
|---|---|
| author | Wilhelm Gottschall Florent Ailloud Christine Josenhans Sebastian Suerbaum |
| author_facet | Wilhelm Gottschall Florent Ailloud Christine Josenhans Sebastian Suerbaum |
| author_sort | Wilhelm Gottschall |
| collection | DOAJ |
| description | ABSTRACT Helicobacter pylori genomes contain a large and variable portfolio of methyltransferases (MTases), creating a highly diverse methylome. Here, we characterize a highly conserved ATTAAT-specific MTase, M.Hpy99XIX (H. pylori strain J99, alternative designations in other strains, M.HpyAVII and M.HpyPVII), the only H. pylori MTase never associated with an endonuclease (“orphan” MTase). Inactivation of M.Hpy99XIX resulted in a significant change in the transcription of >100 genes, despite the fact that only a small subset of their promoter regions contained an ATTAAT target motif. Patterns of transcriptional change showed significant correlations with changes reported for H. pylori mutants in the regulators involved in iron regulation. MTase inactivation also caused a higher susceptibility to diverse metal ions as well as iron chelation and oxidative stress. These phenotypes could be traced back to the methylation of single motifs in the promoter regions of iron transporters frpB1 and fecA1. Altogether, methylation of individual motifs in promoters can have a large downstream effect, causing major changes to metabolic pathways. These findings suggest that the methylome represents a universal and dynamic interface connecting genome diversity and transcriptional regulation. Very recently, a new ecospecies of H. pylori, Hardy, has been reported. M.Hpy99XIX is present in the majority of “normal” (Ubiquitous) H. pylori strains, whereas no single Hardy strain contained this gene, consistent with other reported differences between Hardy and Ubiquitous strains related to iron/metal homeostasis. ATTAAT methylation is intricately connected with the bacterial transcriptional network, highlighting the important role of bacterial epigenetic modifications in bacterial physiology and pathogenesis.IMPORTANCEHelicobacter pylori has one of the largest repertoires of methyltransferases. Methylation has been associated with multiple functions in H. pylori, including the defense against foreign DNA and transcriptional regulation. Regulation of gene expression by methylation has the potential to influence many distant genes across the genome via target motifs in proximity to transcription start sites. Here, we sought to understand the role of M.Hpy99XIX, an orphan methyltransferase targeting the ATTAAT motif that is highly conserved in H. pylori. We show that by directly regulating specific genes involved in iron uptake via methylated ATTAAT motifs, M.Hpy99XIX has a significant effect on iron homeostasis by triggering the canonical iron regulatory pathway. Furthermore, we show that M.Hpy99XIX appears to have been acquired after the split between the two ecospecies of H. pylori, suggesting that its role in the tuning of iron homeostasis might have contributed to this divergence. |
| format | Article |
| id | doaj-art-66607e81a5e84fddbf0ea386e41dbb55 |
| institution | DOAJ |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-66607e81a5e84fddbf0ea386e41dbb552025-08-20T02:40:18ZengAmerican Society for MicrobiologymBio2150-75112025-07-0116710.1128/mbio.01209-25The Helicobacter pylori orphan ATTAAT-specific methyltransferase M.Hpy99XIX plays a central role in the coordinated regulation of genes involved in iron metabolismWilhelm Gottschall0Florent Ailloud1Christine Josenhans2Sebastian Suerbaum3Medical Microbiology and Hospital Epidemiology , Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Munich, GermanyMedical Microbiology and Hospital Epidemiology , Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Munich, GermanyMedical Microbiology and Hospital Epidemiology , Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Munich, GermanyMedical Microbiology and Hospital Epidemiology , Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Munich, GermanyABSTRACT Helicobacter pylori genomes contain a large and variable portfolio of methyltransferases (MTases), creating a highly diverse methylome. Here, we characterize a highly conserved ATTAAT-specific MTase, M.Hpy99XIX (H. pylori strain J99, alternative designations in other strains, M.HpyAVII and M.HpyPVII), the only H. pylori MTase never associated with an endonuclease (“orphan” MTase). Inactivation of M.Hpy99XIX resulted in a significant change in the transcription of >100 genes, despite the fact that only a small subset of their promoter regions contained an ATTAAT target motif. Patterns of transcriptional change showed significant correlations with changes reported for H. pylori mutants in the regulators involved in iron regulation. MTase inactivation also caused a higher susceptibility to diverse metal ions as well as iron chelation and oxidative stress. These phenotypes could be traced back to the methylation of single motifs in the promoter regions of iron transporters frpB1 and fecA1. Altogether, methylation of individual motifs in promoters can have a large downstream effect, causing major changes to metabolic pathways. These findings suggest that the methylome represents a universal and dynamic interface connecting genome diversity and transcriptional regulation. Very recently, a new ecospecies of H. pylori, Hardy, has been reported. M.Hpy99XIX is present in the majority of “normal” (Ubiquitous) H. pylori strains, whereas no single Hardy strain contained this gene, consistent with other reported differences between Hardy and Ubiquitous strains related to iron/metal homeostasis. ATTAAT methylation is intricately connected with the bacterial transcriptional network, highlighting the important role of bacterial epigenetic modifications in bacterial physiology and pathogenesis.IMPORTANCEHelicobacter pylori has one of the largest repertoires of methyltransferases. Methylation has been associated with multiple functions in H. pylori, including the defense against foreign DNA and transcriptional regulation. Regulation of gene expression by methylation has the potential to influence many distant genes across the genome via target motifs in proximity to transcription start sites. Here, we sought to understand the role of M.Hpy99XIX, an orphan methyltransferase targeting the ATTAAT motif that is highly conserved in H. pylori. We show that by directly regulating specific genes involved in iron uptake via methylated ATTAAT motifs, M.Hpy99XIX has a significant effect on iron homeostasis by triggering the canonical iron regulatory pathway. Furthermore, we show that M.Hpy99XIX appears to have been acquired after the split between the two ecospecies of H. pylori, suggesting that its role in the tuning of iron homeostasis might have contributed to this divergence.https://journals.asm.org/doi/10.1128/mbio.01209-25Helicobacter pyloriDNA methylationtranscriptomebacterial epigeneticspromotersgenomics |
| spellingShingle | Wilhelm Gottschall Florent Ailloud Christine Josenhans Sebastian Suerbaum The Helicobacter pylori orphan ATTAAT-specific methyltransferase M.Hpy99XIX plays a central role in the coordinated regulation of genes involved in iron metabolism mBio Helicobacter pylori DNA methylation transcriptome bacterial epigenetics promoters genomics |
| title | The Helicobacter pylori orphan ATTAAT-specific methyltransferase M.Hpy99XIX plays a central role in the coordinated regulation of genes involved in iron metabolism |
| title_full | The Helicobacter pylori orphan ATTAAT-specific methyltransferase M.Hpy99XIX plays a central role in the coordinated regulation of genes involved in iron metabolism |
| title_fullStr | The Helicobacter pylori orphan ATTAAT-specific methyltransferase M.Hpy99XIX plays a central role in the coordinated regulation of genes involved in iron metabolism |
| title_full_unstemmed | The Helicobacter pylori orphan ATTAAT-specific methyltransferase M.Hpy99XIX plays a central role in the coordinated regulation of genes involved in iron metabolism |
| title_short | The Helicobacter pylori orphan ATTAAT-specific methyltransferase M.Hpy99XIX plays a central role in the coordinated regulation of genes involved in iron metabolism |
| title_sort | helicobacter pylori orphan attaat specific methyltransferase m hpy99xix plays a central role in the coordinated regulation of genes involved in iron metabolism |
| topic | Helicobacter pylori DNA methylation transcriptome bacterial epigenetics promoters genomics |
| url | https://journals.asm.org/doi/10.1128/mbio.01209-25 |
| work_keys_str_mv | AT wilhelmgottschall thehelicobacterpyloriorphanattaatspecificmethyltransferasemhpy99xixplaysacentralroleinthecoordinatedregulationofgenesinvolvedinironmetabolism AT florentailloud thehelicobacterpyloriorphanattaatspecificmethyltransferasemhpy99xixplaysacentralroleinthecoordinatedregulationofgenesinvolvedinironmetabolism AT christinejosenhans thehelicobacterpyloriorphanattaatspecificmethyltransferasemhpy99xixplaysacentralroleinthecoordinatedregulationofgenesinvolvedinironmetabolism AT sebastiansuerbaum thehelicobacterpyloriorphanattaatspecificmethyltransferasemhpy99xixplaysacentralroleinthecoordinatedregulationofgenesinvolvedinironmetabolism AT wilhelmgottschall helicobacterpyloriorphanattaatspecificmethyltransferasemhpy99xixplaysacentralroleinthecoordinatedregulationofgenesinvolvedinironmetabolism AT florentailloud helicobacterpyloriorphanattaatspecificmethyltransferasemhpy99xixplaysacentralroleinthecoordinatedregulationofgenesinvolvedinironmetabolism AT christinejosenhans helicobacterpyloriorphanattaatspecificmethyltransferasemhpy99xixplaysacentralroleinthecoordinatedregulationofgenesinvolvedinironmetabolism AT sebastiansuerbaum helicobacterpyloriorphanattaatspecificmethyltransferasemhpy99xixplaysacentralroleinthecoordinatedregulationofgenesinvolvedinironmetabolism |