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

Publication date: Available online 17 January 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Fabio R. Melo, Ola Wallerman, Aida Paivandy, Gabriela Calounova, Ann-Marie Gustafson, Benjamin R. Sabari, Giuliano Zabucchi, C David Allis, Gunnar Pejler
BackgroundMast 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.ObjectiveConsidering 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.MethodsMast 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.ResultsWe 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.ConclusionThese 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.

Graphical abstract

Teaser

Tryptase is mainly implicated in events downstream of mast cell degranulation. Here we show that tryptase additionally has a role in intranuclear core histone processing, thereby affecting epigenetic regulation and cellular differentiation in mast cells.


http://ift.tt/2iQwuxo