Modifications at K31 on the lateral surface of histone H4 contribute to genome structure and expression in apicomplexan parasites
- INSERM, France
- Institut Pasteur, France
- CEA, France
- CNRS, France
Abstract
An unusual genome architecture characterizes the two related human parasitic pathogens Plasmodium falciparum and Toxoplasma gondii. A major fraction of the bulk parasite genome is packaged as transcriptionally permissive euchromatin with few loci embedded in silenced heterochromatin. Primary chromatin shapers include histone modifications at the nucleosome lateral surface close to the DNA but their mode of action remains unclear. We now identify versatile modifications at Lys31 within the globular domain of histone H4 that crucially determine genome organization and expression in Apicomplexa parasites. H4K31 acetylation at the promoter correlates with, and perhaps directly regulates, gene expression in both parasites. In contrast, monomethylated H4K31 is enriched in the core body of T. gondii active genes but inversely correlates with transcription while being unexpectedly enriched at transcriptionally inactive pericentromeric heterochromatin in P. falciparum, a region devoid of the characteristic H3K9me3 histone mark and its downstream effector HP1.
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Article and author information
Author details
Mohamed-ali Hakimi
Funding
European Commission (ERC Consolidator Grant No. 614880)
- Fabien Sindikubwabo
- Dominique Cannella
- Mohamed-ali Hakimi
European Commission (ERC AdG No. 670301)
- Artur Scherf
Agence Nationale de la Recherche (ANR-10-INBS-08-01)
- Lucid Belmudes
- Yohann Couté
Agence Nationale de la Recherche (LABEX PARAFRAP ANR-11-LABX-0024)
- Fabien Sindikubwabo
- Shuai Ding
- Tahir Hussain
- Dominique Cannella
- Andrés Palencia
- Alexandre Bougdour
- Artur Scherf
- Mohamed-ali Hakimi
Agence Nationale de la Recherche (ANR-12-BSV3-0009-01)
- Dominique Cannella
- Andrés Palencia
- Alexandre Bougdour
- Mohamed-ali Hakimi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Sindikubwabo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Modifications at K31 on the lateral surface of histone H4 contribute to genome structure and expression in apicomplexan parasites
eLife 6:e29391.
https://doi.org/10.7554/eLife.29391
Further reading
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- Medicine
- Microbiology and Infectious Disease
Background:
Under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics.
Methods:
We searched CENTRAL, EMBASE, and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to 24 November 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. Patients were considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials’ risk of bias was assessed with the Cochrane tool.
Results:
42 trials were eligible and 29, including 5054 patients, qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68–2.25), with substantial between-study heterogeneity (I2=77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions.
Conclusions:
The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.
Funding:
Support from the Swiss National Science Foundation (grant 310030B_176401 (SB, BS, CW), grant 32FP30-174281 (ME), grant 324730_207957 (RDK)) and from the National Institute of Allergy and Infectious Diseases (NIAID, cooperative agreement AI069924 (ME)) is gratefully acknowledged.
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- Evolutionary Biology
- Microbiology and Infectious Disease
The global rise of antibiotic resistance calls for new drugs against bacterial pathogens. A common approach is to search for natural compounds deployed by microbes to inhibit competitors. Here, we show that the iron-chelating pyoverdines, siderophores produced by environmental Pseudomonas spp., have strong antibacterial properties by inducing iron starvation and growth arrest in pathogens. A screen of 320 natural Pseudomonas isolates used against 12 human pathogens uncovered several pyoverdines with particularly high antibacterial properties and distinct chemical characteristics. The most potent pyoverdine effectively reduced growth of the pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Staphylococcus aureus in a concentration- and iron-dependent manner. Pyoverdine increased survival of infected Galleria mellonella host larvae and showed low toxicity for the host, mammalian cell lines, and erythrocytes. Furthermore, experimental evolution of pathogens combined with whole-genome sequencing revealed limited resistance evolution compared to an antibiotic. Thus, pyoverdines from environmental strains have the potential to become a new class of sustainable antibacterials against specific human pathogens.
