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.
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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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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- Microbiology and Infectious Disease
- Structural Biology and Molecular Biophysics
African trypanosomes replicate within infected mammals where they are exposed to the complement system. This system centres around complement C3, which is present in a soluble form in serum but becomes covalently deposited onto the surfaces of pathogens after proteolytic cleavage to C3b. Membrane-associated C3b triggers different complement-mediated effectors which promote pathogen clearance. To counter complement-mediated clearance, African trypanosomes have a cell surface receptor, ISG65, which binds to C3b and which decreases the rate of trypanosome clearance in an infection model. However, the mechanism by which ISG65 reduces C3b function has not been determined. We reveal through cryogenic electron microscopy that ISG65 has two distinct binding sites for C3b, only one of which is available in C3 and C3d. We show that ISG65 does not block the formation of C3b or the function of the C3 convertase which catalyses the surface deposition of C3b. However, we show that ISG65 forms a specific conjugate with C3b, perhaps acting as a decoy. ISG65 also occludes the binding sites for complement receptors 2 and 3, which may disrupt recruitment of immune cells, including B cells, phagocytes, and granulocytes. This suggests that ISG65 protects trypanosomes by combining multiple approaches to dampen the complement cascade.
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