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Tryptase-catalyzed core histone truncation: A novel epigenetic regulatory mechanism in mast cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
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2017 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 140, no 2, 474-485 p.Article in journal (Refereed) Published
Abstract [en]

Background: Mast cells are key effector cells in allergic reactions. When activated to degranulate, they release a plethora of bioactive compounds from their secretory granules, including mast cell-restricted proteases such as tryptase. In a previous study, we showed that tryptase, in addition to its intragranular location, can be found within the nuclei of mast cells where it truncates core histones at their N-terminal ends. Objective: Considering that the N-terminal portions of the core histones constitute sites for posttranslational modifications of major epigenetic impact, we evaluated whether histone truncation by tryptase could have an impact on epigenetic events in mast cells. Methods: Mast cells were cultured from wild-type and tryptase null mice, followed by an assessment of their profile of epigenetic histone modifications and their phenotypic characteristics. Results: We show that tryptase truncates nucleosomal histone 3 and histone 2B (H2B) and that its absence results in accumulation of the epigenetic mark, lysine 5-acetylated H2B. Intriguingly, the accumulation of lysine 5-acetylated H2B was cell age-dependent and was associated with a profound upregulation of markers of non-mast cell lineages, loss of proliferative control, chromatin remodeling as well as extensive morphological alterations. Conclusions: These findings introduce tryptase-catalyzed histone clipping as a novel epigenetic regulatory mechanism, which in the mast cell context may be crucial for maintaining cellular identity.

Place, publisher, year, edition, pages
MOSBY-ELSEVIER , 2017. Vol. 140, no 2, 474-485 p.
Keyword [en]
Mast cells, epigenetics, core histones, histone acetylation, tryptase, mMCP6, secretory granules, serglycin, serglycin proteoglycan, H2B, H2BK5ac
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-335673DOI: 10.1016/j.jaci.2016.11.044ISI: 000406855500020PubMedID: 28108335OAI: oai:DiVA.org:uu-335673DiVA: diva2:1168198
Funder
Swedish Research Council, K2014-68X-0913-23-4Swedish Cancer Society, CAN 2013/423Swedish Heart Lung Foundation, 20150290Swedish Research Council Formas, 221-2012-1098Torsten Söderbergs stiftelse, M80/14NIH (National Institute of Health), R01-GM40922
Available from: 2017-12-20 Created: 2017-12-20 Last updated: 2017-12-20Bibliographically approved

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Melo, Fabio R.Wallerman, OlaPaivandy, AidaGustafson, Ann-MariePejler, Gunnar

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