H3K4me3 Histone ChIP-Seq Analysis Reveals Molecular Mechanisms Responsible for Neutrophil Dysfunction in HIV-Infected Individuals
Peripheral neutrophils in HIV-infected individuals are characterized by impairment of chemotaxis, phagocytosis, bactericidal activity, and oxidative burst ability regardless of whether patients are receiving antiretroviral therapy or not. Neutrophil dysfunction leads not only to increased susceptibi...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.682094/full |
| _version_ | 1818589479639711744 |
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| author | Paweł Piatek Maciej Tarkowski Magdalena Namiecinska Agostino Riva Marek Wieczorek Sylwia Michlewska Justyna Dulska Małgorzata Domowicz Małgorzata Kulińska-Michalska Natalia Lewkowicz Przemysław Lewkowicz |
| author_facet | Paweł Piatek Maciej Tarkowski Magdalena Namiecinska Agostino Riva Marek Wieczorek Sylwia Michlewska Justyna Dulska Małgorzata Domowicz Małgorzata Kulińska-Michalska Natalia Lewkowicz Przemysław Lewkowicz |
| author_sort | Paweł Piatek |
| collection | DOAJ |
| description | Peripheral neutrophils in HIV-infected individuals are characterized by impairment of chemotaxis, phagocytosis, bactericidal activity, and oxidative burst ability regardless of whether patients are receiving antiretroviral therapy or not. Neutrophil dysfunction leads not only to increased susceptibility to opportunistic infections but also to tissue damage through the release of reactive oxygen species (ROS), proteases, and other potentially harmful effector molecules contributing to AIDS progression. In this study, we demonstrated high levels of histone H3 lysine K4 trimethylated (H3K4me3) and dysregulation of DNA transcription in circulating neutrophils of HIV-infected subjects. This dysregulation was accompanied by a deficient response of neutrophils to LPS, impaired cytokine/chemokine/growth factor synthesis, and increased apoptosis. Chromatin immunoprecipitation sequencing (ChIPseq) H3K4me3 histone analysis revealed that the most spectacular abnormalities were observed in the exons, introns, and promoter-TSS regions. Bioinformatic analysis of Gene Ontology, including biological processes, molecular function, and cellular components, demonstrated that the main changes were related to the genes responsible for cell activation, cytokine production, adhesive molecule expression, histone remodeling via upregulation of methyltransferase process, and downregulation of NF-κB transcription factor in canonical pathways. Abnormalities within H3K4me3 implicated LPS-mediated NF-κB canonical activation pathway that was a result of low amounts of κB DNA sites within histone H3K4me3, low NF-κB (p65 RelA) and TLR4 mRNA expression, and reduced free NF-κB (p65 RelA) accumulation in the nucleus. Genome-wide survey of H3K4me3 provided evidence that chromatin modifications lead to an impairment within the canonical NF-κB cell activation pathway causing the neutrophil dysfunction observed in HIV-infected individuals. |
| first_indexed | 2024-12-16T09:41:18Z |
| format | Article |
| id | doaj.art-539a9c3e5136423ba3e89aff0fa95b87 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-16T09:41:18Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-539a9c3e5136423ba3e89aff0fa95b872022-12-21T22:36:16ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-07-011210.3389/fimmu.2021.682094682094H3K4me3 Histone ChIP-Seq Analysis Reveals Molecular Mechanisms Responsible for Neutrophil Dysfunction in HIV-Infected IndividualsPaweł Piatek0Maciej Tarkowski1Magdalena Namiecinska2Agostino Riva3Marek Wieczorek4Sylwia Michlewska5Justyna Dulska6Małgorzata Domowicz7Małgorzata Kulińska-Michalska8Natalia Lewkowicz9Przemysław Lewkowicz10Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Lodz, PolandDepartment of Biomedical and Clinical Sciences, ‘Luigi Sacco’, University of Milan, Milan, ItalyDepartment of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Lodz, PolandDepartment of Biomedical and Clinical Sciences, ‘Luigi Sacco’, University of Milan, Milan, ItalyDepartment of Neurobiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, PolandLaboratory of Microscopic Imaging and Specialized Biological Techniques, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, PolandGenomed SA, Warsaw, PolandDepartment of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Lodz, PolandDepartment of Periodontology and Oral Mucosal Diseases, Medical University of Lodz, Lodz, PolandDepartment of Periodontology and Oral Mucosal Diseases, Medical University of Lodz, Lodz, PolandDepartment of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Lodz, PolandPeripheral neutrophils in HIV-infected individuals are characterized by impairment of chemotaxis, phagocytosis, bactericidal activity, and oxidative burst ability regardless of whether patients are receiving antiretroviral therapy or not. Neutrophil dysfunction leads not only to increased susceptibility to opportunistic infections but also to tissue damage through the release of reactive oxygen species (ROS), proteases, and other potentially harmful effector molecules contributing to AIDS progression. In this study, we demonstrated high levels of histone H3 lysine K4 trimethylated (H3K4me3) and dysregulation of DNA transcription in circulating neutrophils of HIV-infected subjects. This dysregulation was accompanied by a deficient response of neutrophils to LPS, impaired cytokine/chemokine/growth factor synthesis, and increased apoptosis. Chromatin immunoprecipitation sequencing (ChIPseq) H3K4me3 histone analysis revealed that the most spectacular abnormalities were observed in the exons, introns, and promoter-TSS regions. Bioinformatic analysis of Gene Ontology, including biological processes, molecular function, and cellular components, demonstrated that the main changes were related to the genes responsible for cell activation, cytokine production, adhesive molecule expression, histone remodeling via upregulation of methyltransferase process, and downregulation of NF-κB transcription factor in canonical pathways. Abnormalities within H3K4me3 implicated LPS-mediated NF-κB canonical activation pathway that was a result of low amounts of κB DNA sites within histone H3K4me3, low NF-κB (p65 RelA) and TLR4 mRNA expression, and reduced free NF-κB (p65 RelA) accumulation in the nucleus. Genome-wide survey of H3K4me3 provided evidence that chromatin modifications lead to an impairment within the canonical NF-κB cell activation pathway causing the neutrophil dysfunction observed in HIV-infected individuals.https://www.frontiersin.org/articles/10.3389/fimmu.2021.682094/fullneutrophilshuman immunodeficiency virusH3K4me3ChIPSeqinnate immunity |
| spellingShingle | Paweł Piatek Maciej Tarkowski Magdalena Namiecinska Agostino Riva Marek Wieczorek Sylwia Michlewska Justyna Dulska Małgorzata Domowicz Małgorzata Kulińska-Michalska Natalia Lewkowicz Przemysław Lewkowicz H3K4me3 Histone ChIP-Seq Analysis Reveals Molecular Mechanisms Responsible for Neutrophil Dysfunction in HIV-Infected Individuals Frontiers in Immunology neutrophils human immunodeficiency virus H3K4me3 ChIPSeq innate immunity |
| title | H3K4me3 Histone ChIP-Seq Analysis Reveals Molecular Mechanisms Responsible for Neutrophil Dysfunction in HIV-Infected Individuals |
| title_full | H3K4me3 Histone ChIP-Seq Analysis Reveals Molecular Mechanisms Responsible for Neutrophil Dysfunction in HIV-Infected Individuals |
| title_fullStr | H3K4me3 Histone ChIP-Seq Analysis Reveals Molecular Mechanisms Responsible for Neutrophil Dysfunction in HIV-Infected Individuals |
| title_full_unstemmed | H3K4me3 Histone ChIP-Seq Analysis Reveals Molecular Mechanisms Responsible for Neutrophil Dysfunction in HIV-Infected Individuals |
| title_short | H3K4me3 Histone ChIP-Seq Analysis Reveals Molecular Mechanisms Responsible for Neutrophil Dysfunction in HIV-Infected Individuals |
| title_sort | h3k4me3 histone chip seq analysis reveals molecular mechanisms responsible for neutrophil dysfunction in hiv infected individuals |
| topic | neutrophils human immunodeficiency virus H3K4me3 ChIPSeq innate immunity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.682094/full |
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