Histone variant H2B.Z acetylation is necessary for maintenance of Toxoplasma gondii biological fitness |
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| Institution: | 1. Laboratorio de Parasitología Molecular, INTECH, CONICET-UNSAM, Av. Intendente Marino Km. 8.2, C.C 164, B7130IIWA, Chascomús, Prov. Buenos Aires, Argentina;2. Laboratorio de Bioquímica y Biología Celular de Parásitos, INTECH, CONICET-UNSAM, Av. Intendente Marino Km. 8.2, C.C 164, B7130IIWA Chascomús, Prov. Buenos Aires, Argentina;3. Núcleo de Biotecnología Curauma, Pontificia Universidad Católica de Valparaiso, Av. Universidad 330 Curauma, Valparaiso, Chile;4. Department of Biology and VBRN, University of Vermont, VT, USA;5. Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;6. Department of Pharmacology and Toxicology, Indiana School of Medicine, Indianapolis, IN 46202, USA;1. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;2. Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada;3. Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada;4. Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec H3C 3J7, Canada;5. Department of Chemistry, Université de Montréal, Montréal, Quebec H3C 3J7, Canada;6. Département de Pathologie et Biologie Cellulaire, Université de Montréal, QC, Canada;1. Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA;2. INSERM U1242, “Oncogenesis, Stress, Signaling”, Université de Rennes, Rennes, France;3. Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France;4. Imperial College London, London, UK;5. Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France;1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou, Jiangsu 215123, PR China;2. Key Laboratory of Pesticides & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, Hubei 430079, PR China;3. School of Biology and Basic Medical Science, Soochow University, Suzhou, Jiangsu 215021, PR China;1. Department of Cell Biology and Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China;2. State Key Laboratory of Proteomics, Beijing Proteome Reesearch Center, National Center for Protein Sciences Beijing, Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Institute of Lifeomics, Beijing 102206, China;3. Anhui Medical University School of Basic Medicine, Hefei 230032, Anhui, China;4. Department of Biomedicine, School of Medicine, Guizhou University, Guiyang 550025, China;5. Department of Toxicology, School of Public Health, China Medical University, Shenyang, 110122, PR China |
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| Abstract: | Through regulation of DNA packaging, histone proteins are fundamental to a wide array of biological processes. A variety of post-translational modifications (PTMs), including acetylation, constitute a proposed histone code that is interpreted by “reader” proteins to modulate chromatin structure. Canonical histones can be replaced with variant versions that add an additional layer of regulatory complexity. The protozoan parasite Toxoplasma gondii is unique among eukaryotes in possessing a novel variant of H2B designated H2B.Z. The combination of PTMs and the use of histone variants are important for gene regulation in T. gondii, offering new targets for drug development. In this work, T. gondii parasites were generated in which the 5 N-terminal acetylatable lysines in H2B.Z were mutated to either alanine (c-Myc-A) or arginine (c-Myc-R). The c-Myc-A mutant displayed no phenotype over than a mild defect in its ability to kill mice. The c-Myc-R mutant presented an impaired ability to grow and an increase in differentiation to latent bradyzoites. The c-Myc-R mutant was also more sensitive to DNA damage, displayed no virulence in mice, and provided protective immunity against future infection. While nucleosome composition was unaltered, key genes were abnormally expressed during in vitro bradyzoite differentiation. Our results show that regulation of the N-terminal positive charge patch of H2B.Z is important for these processes. We also show that acetylated N-terminal H2B.Z interacts with some unique proteins compared to its unacetylated counterpart; the acetylated peptide pulled down proteins associated with chromosome maintenance/segregation and cell cycle, suggesting a link between H2B.Z acetylation status and mitosis. |
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