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Tryptase-catalyzed core histone truncation: a novel epigenetic regulatory mechanism in mast cells.

Research paper by Fabio R FR Melo, Ola O Wallerman, Aida A Paivandy, Gabriela G Calounova, Ann-Marie AM Gustafson, Benjamin R BR Sabari, Giuliano G Zabucchi, C David CD Allis, Gunnar G Pejler

Indexed on: 22 Jan '17Published on: 22 Jan '17Published in: Journal of Allergy and Clinical Immunology



Abstract

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.Considering that the N-terminal portions of the core histones constitute sites for posttranslational modifications of major epigenetic impact, we here evaluated whether histone truncation by tryptase could have an impact on epigenetic events in mast cells.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.We show that tryptase truncates nucleosomal histone 3 (H3) and H2B and that its absence results in accumulation of the epigenetic mark, lysine 5-acetylated H2B (H2BK5ac). Intriguingly, the accumulation of H2BK5ac 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.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.