Modifications at K31 on the lateral surface of histone H4 contribute to genome structure and expression in apicomplexan parasites
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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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
- Cyrille Y Botté
- Artur Scherf
- Mohamed-ali Hakimi
Agence Nationale de la Recherche (ANR-12-BSV3-0009-01)
- Dominique Cannella
- Andrés Palencia
- Alexandre Bougdour
- Mohamed-ali Hakimi
Agence Nationale de la Recherche (ANR-12-PDOC-0028)
- Cyrille Y Botté
CNRS-INSERM-Fondation FINOVI (Atip-Avenir Program Project Apicolipid)
- Cyrille Y Botté
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Daniel Zilberman, University of California, Berkeley, United States
Version history
- Received: June 7, 2017
- Accepted: November 2, 2017
- Accepted Manuscript published: November 4, 2017 (version 1)
- Accepted Manuscript updated: November 7, 2017 (version 2)
- Version of Record published: November 14, 2017 (version 3)
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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Further reading
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- Microbiology and Infectious Disease
It is currently unknown whether all Plasmodium falciparum-infected mosquitoes are equally infectious. We assessed sporogonic development using cultured gametocytes in the Netherlands and naturally circulating strains in Burkina Faso. We quantified the number of sporozoites expelled into artificial skin in relation to intact oocysts, ruptured oocysts, and residual salivary gland sporozoites. In laboratory conditions, higher total sporozoite burden was associated with shorter duration of sporogony (p<0.001). Overall, 53% (116/216) of infected Anopheles stephensi mosquitoes expelled sporozoites into artificial skin with a median of 136 expelled sporozoites (interquartile range [IQR], 34–501). There was a strong positive correlation between ruptured oocyst number and salivary gland sporozoite load (ρ = 0.8; p<0.0001) and a weaker positive correlation between salivary gland sporozoite load and number of sporozoites expelled (ρ = 0.35; p=0.0002). In Burkina Faso, Anopheles coluzzii mosquitoes were infected by natural gametocyte carriers. Among salivary gland sporozoite positive mosquitoes, 89% (33/37) expelled sporozoites with a median of 1035 expelled sporozoites (IQR, 171–2969). Again, we observed a strong correlation between ruptured oocyst number and salivary gland sporozoite load (ρ = 0.9; p<0.0001) and a positive correlation between salivary gland sporozoite load and the number of sporozoites expelled (ρ = 0.7; p<0.0001). Several mosquitoes expelled multiple parasite clones during probing. Whilst sporozoite expelling was regularly observed from mosquitoes with low infection burdens, our findings indicate that mosquito infection burden is positively associated with the number of expelled sporozoites. Future work is required to determine the direct implications of these findings for transmission potential.
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- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
Cyclic nucleotide binding domains (CNB) confer allosteric regulation by cAMP or cGMP to many signaling proteins, including PKA and PKG. PKA of phylogenetically distant Trypanosoma is the first exception as it is cyclic nucleotide-independent and responsive to nucleoside analogues (Bachmaier et al., 2019). Here, we show that natural nucleosides inosine, guanosine and adenosine are nanomolar affinity CNB ligands and activators of PKA orthologs of the important tropical pathogens Trypanosoma brucei, Trypanosoma cruzi, and Leishmania. The sequence and structural determinants of binding affinity, -specificity and kinase activation of PKAR were established by structure-activity relationship (SAR) analysis, co-crystal structures and mutagenesis. Substitution of two to three amino acids in the binding sites is sufficient for conversion of CNB domains from nucleoside to cyclic nucleotide specificity. In addition, a trypanosomatid-specific C-terminal helix (αD) is required for high affinity binding to CNB-B. The αD helix functions as a lid of the binding site that shields ligands from solvent. Selectivity of guanosine for CNB-B and of adenosine for CNB-A results in synergistic kinase activation at low nanomolar concentration. PKA pulldown from rapid lysis establishes guanosine as the predominant ligand in vivo in T. brucei bloodstream forms, whereas guanosine and adenosine seem to synergize in the procyclic developmental stage in the insect vector. We discuss the versatile use of CNB domains in evolution and recruitment of PKA for novel nucleoside-mediated signaling.