1. Microbiology and Infectious Disease
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Modifications at K31 on the lateral surface of histone H4 contribute to genome structure and expression in apicomplexan parasites

Research Article
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Cite this article as: eLife 2017;6:e29391 doi: 10.7554/eLife.29391

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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Author details

  1. Fabien Sindikubwabo

    Institute for Advanced Biosciences - U1209, INSERM, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Shuai Ding

    Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Tahir Hussain

    Institute for Advanced Biosciences - U1209, INSERM, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Philippe Ortet

    UMR 7265, CEA, Cadarache, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Mohamed Barakat

    UMR 7265, CEA, Cadarache, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Sebastian Baumgarten

    Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Dominique Cannella

    Institute for Advanced Biosciences - U1209, INSERM, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Andrés Palencia

    Institute for Advanced Biosciences - U1209, INSERM, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1805-319X
  9. Alexandre Bougdour

    Institute for Advanced Biosciences - U1209, INSERM, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Lucid Belmudes

    BIG-BGE, CEA, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Yohann Couté

    BIG-BGE, CEA, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3896-6196
  12. Isabelle Tardieux

    Institute for Advanced Biosciences - U1209, CNRS, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Cyrille Y Botté

    Institute for Advanced Biosciences - U1209, CNRS, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Artur Scherf

    Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  15. Mohamed-ali Hakimi

    Institute for Advanced Biosciences - U1209, INSERM, Grenoble, France
    For correspondence
    mohamed-ali.hakimi@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2547-8233

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

  1. Daniel Zilberman, University of California, Berkeley, United States

Publication history

  1. Received: June 7, 2017
  2. Accepted: November 2, 2017
  3. Accepted Manuscript published: November 4, 2017 (version 1)
  4. Accepted Manuscript updated: November 7, 2017 (version 2)
  5. 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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    Qi Yan Ang et al.
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    East Asians (EAs) experience worse metabolic health outcomes compared to other ethnic groups at lower body mass indices; however, the potential role of the gut microbiota in contributing to these health disparities remains unknown. We conducted a multi-omic study of 46 lean and obese East Asian and White participants living in the San Francisco Bay Area, revealing marked differences between ethnic groups in bacterial richness and community structure. White individuals were enriched for the mucin-degrading Akkermansia muciniphila. East Asian subjects had increased levels of multiple bacterial phyla, fermentative pathways detected by metagenomics, and the short-chain fatty acid end-products acetate, propionate, and isobutyrate. Differences in the gut microbiota between the East Asian and White subjects could not be explained by dietary intake, were more pronounced in lean individuals, and were associated with current geographical location. Microbiome transplantations into germ-free mice demonstrated stable diet- and host genotype-independent differences between the gut microbiotas of East Asian and White individuals that differentially impact host body composition. Taken together, our findings add to the growing body of literature describing microbiome variations between ethnicities and provide a starting point for defining the mechanisms through which the microbiome may shape disparate health outcomes in East Asians.

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    For many intracellular pathogens, the phagosome is the site of events and interactions that shape infection outcome. Phagosomal membrane damage, in particular, is proposed to benefit invading pathogens. To define the innate immune consequences of this damage, we profiled macrophage transcriptional responses to wild-type Mycobacterium tuberculosis (Mtb) and mutants that fail to damage the phagosomal membrane. We identified a set of genes with enhanced expression in response to the mutants. These genes represented a late component of the TLR2-dependent transcriptional response to Mtb, distinct from an earlier component that included Tnf. Expression of the later component was inherent to TLR2 activation, dependent upon endosomal uptake, and enhanced by phagosome acidification. Canonical Mtb virulence factors that contribute to phagosomal membrane damage blunted phagosome acidification and undermined the endosome-specific response. Profiling cell survival and bacterial growth in macrophages demonstrated that the attenuation of these mutants is partially dependent upon TLR2. Further, TLR2 contributed to the attenuated phenotype of one of these mutants in a murine model of infection. These results demonstrate two distinct components of the TLR2 response and identify a component dependent upon endosomal uptake as a point where pathogenic bacteria interfere with the generation of effective inflammation. This interference promotes tuberculosis (TB) pathogenesis in both macrophage and murine infection models.